Benzenesulfonamide compounds and their use

ABSTRACT

The invention relates to azetidinyl, pyrrolidinyl, piperidinyl, and hexahydroazepinyl compounds of Formula I and pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein R 1 -R 3  and Z are defined as set forth in the specification. The invention is also directed to the use compounds of Formula I to treat, prevent or ameliorate a disorder responsive to the blockade of calcium channels, and particularly N-type calcium channels. Compounds of the present invention are especially useful for treating pain.

This application is a National Stage of International Application No.PCT/EP2007/053053, filed Mar. 29, 2007, which claims the benefit of U.S.Provisional Application Nos. 60/786,688, filed Mar. 29, 2006, and60/791,428, filed Apr. 13, 2006.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is in the field of medicinal chemistry. The inventionrelates to novel azetidinyl, pyrrolidinyl, piperidinyl, andhexahydroazepinyl compounds and the discovery that these compounds actas blockers of calcium (Ca²⁺) channels.

2. Background Art

Calcium ions play fundamental roles in the regulation of many cellularprocesses. It is therefore essential that their intracellular levels bemaintained under strict, yet dynamic control (Davila, H. M., Annals ofthe New York Academy of Sciences, pp. 102-117 (1999)). Voltage-gatedcalcium channels (VGCC) serve as one of the important mechanisms forfast calcium influx into the cell. Calcium channels arehetero-oligomeric proteins consisting of a pore-forming subunit (α1),which is able to form functional channels on its own in heterologousexpression systems, and a set of auxiliary or regulatory subunits.Calcium channels have been classified based on their pharmacologicaland/or electrophysiological properties. The classification ofvoltage-gated calcium channels divides them into three groups: (i) highvoltage-activated (HVA) channels, which include L-, N-, P-, and Q-types;(ii) intermediate (IVA) voltage-activated R-type channels; and (iii) lowvoltage-activated (LVA) T-type channels (Davila, supra). Voltage-gatedcalcium channels (VGCC) are also known as voltage-dependent calciumchannels (VDCC) or voltage-sensitive calcium channels (VSCC).

Voltage-sensitive calcium channels (VSCC) regulate intracellular calciumconcentration, which affects various important neuronal functions suchas cellular excitability, neurotransmitter release, hormone secretion,intracellular metabolism, neurosecretory activity and gene expression(Hu et al., Bioorganic & Medicinal Chemistry 8:1203-1212 (2000)). N-typechannels are found mainly in central and peripheral neurons, beingprimarily located on presynaptic nerve terminals. These channelsregulate the calcium flux required for depolarization-evoked release ofa transmitter from synaptic endings. The transmission of pain signalsfrom the periphery to the central nervous system (CNS) is mediated byN-type calcium channels located in the spinal cord (Song et al, J. Med.Chem. 43:3474-3477 (2000)).

The six types of calcium channels (i.e., L, N, P, Q, R, and T) areexpressed throughout the nervous system (Wallace, M. S., The ClinicalJournal of Pain 16:580-585 (2000)). Voltage-sensitive calcium channelsof the N-type exist in the superficial laminae of the dorsal horn andare thought to modulate nociceptive processing by a central mechanism.Blockade of the N-type calcium channel in the superficial dorsal hornmodulates membrane excitability and inhibits neurotransmitter release,resulting in pain relief. Wallace (supra) suggests that based on animalmodels, N-type calcium channel antagonists have a greater analgesicpotency than sodium channel antagonists.

N-type calcium channel blockers have usefulness for neuroprotection andanalgesia. Ziconotide, which is a selective N-type calcium channelblocker, has been found to have analgesic activity in animal models andneuroprotective activity in focal and global ischemia models (Song etal., supra). Examples of known calcium channel blockers includeflunarizine, fluspirilene, cilnipide, PD 157767, SB-201823, SB-206284,NNC09-0026, and PD 151307 (Hu et al., supra).

Blockade of N-type channels can prevent and/or attenuate subjective painas well as primary and/or secondary hyperalgesia and allodynia in avariety of experimental and clinical conditions (Vanegas, H. et al.,Pain 85:9-18 (2000)). N-type voltage-gated calcium channels (VGCC) playa major role in the release of synaptic mediators such as glutamate,acetylcholine, dopamine, norepinephrine, gamma-aminobutyric acid (GABA)and calcitonin gene-related peptide (CGRP).

Inhibition of voltage-gated L-type calcium channels has been shown to bebeneficial for neuroprotection (Song et al., supra). However, inhibitionof cardiac L-type calcium channels can lead to hypotension. It isbelieved that a rapid and profound lowering of arterial pressure tendsto counteract the neuroprotective effects of L-type calcium channelblockers. A need exists for antagonists that are selective for N-typecalcium channels over L-type calcium channels to avoid potentialhypotensive effects.

Published PCT Application No. WO 02/28346 by Odile et al. describesN-{1-[bis(4-chlorophenyl)methyl]-3-azetidinyl}-4-fluoro-N-methylbenzenesulfonamideandN-{1-[bis(4-chlorophenyl)methyl]-3-azetidinyl}-N-methylbenzenesulfonamideas CB 1 receptor antagonists. U.S. Pat. No. 6,262,046 to Alker et aldescribes 1-diphenylmethyl-3-(N-methylbenzenesulfonamido)azetidine as anintermediate.

U.S. Pat. No. 6,734,176 to Achard et al. describes pharmaceuticalcompositions containing 3-aminoazetidine derivatives useful as CB1-receptor antagonists.

United States Patent Application Publication No. US 2004/00224901 byChaturvedula et al. describesN-{1-[(2R)-2-amino-3-(4-chlorophenyl)propionyl]-(3S)-pyrrolidin-3-yl}-N-cyclohexyl-benzenesulfonamideand[2-[(3S)-3-(benzenesulfonyl-cyclohexylamino)pyrrolidin-1-yl]-(1R)-(4-chlorobenzyl)-2-oxo-ethyl]carbamicacid tert-butyl ester as intermediates.

United States Patent Application Publication No. US 2005/245573 byNeitzel et al. describes4-chloro-N-ethyl-N-[1-(phenylmethyl)-3-pyrrolidinyl]benzenesulfonamideuseful in the treatment of or prevention of congnitive disorders, suchas Alzheimer's disease.

BRIEF SUMMARY OF THE INVENTION

The present invention is related to the use of azetidinyl, pyrrolidinyl,piperidinyl, and hexahydroazepinyl compounds represented by Formula I,below, and the pharmaceutically acceptable salts, prodrugs and solvatesthereof, as blockers of calcium (Ca²⁺) channels. Certain compounds ofFormula I show selectivity as N-type calcium channel blockers.

The invention is also related to treating, preventing or ameliorating adisorder responsive to the blockade of calcium channels in a mammalsuffering from excess activity of said channels by administering aneffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof, as described herein.Specifically, the invention is related to treating, preventing orameliorating a disorder responsive to the blockade of N-type calciumchannels in a mammal suffering from excess activity of said channels byadministering an effective amount of a compound of Formula I, or apharmaceutically acceptable salt, prodrug or solvate thereof, asdescribed herein.

A number of compounds useful in the present invention have not beenheretofore reported. Thus, one aspect of the present invention isdirected to novel compounds of Formula I, as well as theirpharmaceutically acceptable salts, prodrugs and solvates.

Another aspect of the present invention is directed to the use of thenovel compounds of Formula I, and their pharmaceutically acceptablesalts, prodrugs and solvates, as blockers of N-type calcium channels.

A further aspect of the present invention is to provide a method fortreating, preventing or ameliorating stroke, neuronal damage resultingfrom head trauma, epilepsy, pain (e.g., acute pain, chronic pain, whichincludes but is not limited to neuropathic pain and inflammatory pain,or surgical pain), migraine, a mood disorder, schizophrenia, aneurodegenerative disorder (e.g., Alzheimer's disease, amyotrophiclateral sclerosis (ALS), or Parkinson's disease), depression, anxiety, apsychosis, hypertension, or cardiac arrhythmia, by administering aneffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof, to a mammal in need of suchtreatment, prevention or amelioration.

A further aspect of the present invention is to provide a pharmaceuticalcomposition useful for treating, preventing or ameliorating a disorderresponsive to the blockade of calcium ion channels, especially N-typecalcium ion channels, said pharmaceutical composition containing aneffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof, in a mixture with one ormore pharmaceutically acceptable carriers.

Also, an aspect of the invention is to provide a method of modulatingcalcium channels, especially N-type calcium channels, in a mammal,wherein said method comprises administering to the mammal an effectiveamount of at least one compound of Formula I, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof.

A further aspect of the present invention is to provide radiolabeledcompounds of Formula I and the use of such compounds, or theirpharmaceutically acceptable salts, prodrugs or solvates, as radioligandsfor their binding site on the calcium channel.

A further aspect of the invention is to provide a method for screening acandidate compound for the ability to bind to a receptor using a ³H,¹¹C, or ¹⁴C radiolabeled compound of Formula I, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof. This method comprises a)introducing a fixed concentration of the radiolabeled compound to thereceptor to form a mixture; b) titrating the mixture with a candidatecompound; and c) determining the binding of the candidate compound tosaid receptor.

A further aspect of the invention is to provide the use of a compound ofFormula I, or a pharmaceutically acceptable salt, prodrug or solvatethereof, in the manufacture of a medicament for treating, preventing orameliorating stroke, neuronal damage resulting from head trauma,epilepsy, pain, migraine, a mood disorder, schizophrenia, aneurodegenerative disorder, depression, anxiety, a psychosis,hypertension, or cardiac arrhythmia in a mammal. In a preferredembodiment, the invention provides the use of a compound of Formula I,or a pharmaceutically acceptable salt, prodrug or solvate thereof, inthe manufacture of a medicament for treating, preventing or amelioratingacute pain, chronic pain, or surgical pain.

Additional embodiments and advantages of the invention will be set forthin part in the description that follows, and will flow from thedescription, or may be learned by practice of the invention. Theembodiments and advantages of the invention will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims.

It is to be understood that both the foregoing summary and the followingdetailed description are exemplary and explanatory only and are notrestrictive of the invention, as claimed.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present invention is based on the use of compounds ofFormula I, and the pharmaceutically acceptable salts, prodrugs andsolvates thereof, as blockers of Ca²⁺ channels. In view of thisproperty, compounds of Formula I, and the pharmaceutically acceptablesalts, prodrugs and solvates thereof, are useful for treating disordersresponsive to the blockade of calcium ion channels. In one aspect,compounds of Formula I, and the pharmaceutically acceptable salts,prodrugs and solvates thereof, selectively block N-type calcium ionchannels and, thus, are useful for treating disorders responsive to theselective blockade of N-type calcium ion channels.

The compounds useful in this aspect of the invention are compoundsrepresented by Formula I:

and pharmaceutically acceptable salts, prodrugs and solvates thereof,wherein:

R¹ and R² are each independently selected from the group consisting ofhydrogen, alkyl, haloalkyl, halogen, alkoxy, haloalkoxy, cyano, nitro,amino, aminoalkyl, alkylamino, dialkylamino, and hydroxy;

R³ is selected from the group consisting of hydrogen, alkyl, alkenyl,cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylalkyl,3-tetrahydrofuranylalkyl, alkylsulfonylaminoalkyl, aminocarbonylalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cyanoalkyl,carboxyalkyl, and alkoxycarbonylalkyl;

Z is selected from the group consisting of Z¹, Z², Z³, Z⁴, and Z⁵,wherein:

Z¹ is

Z² is

Z³ is—CR⁸R⁹—(CH₂)_(P)-D-R¹⁴;Z⁴ is—SO₂R¹⁵; andZ⁵ is

provided that Z is Z¹, Z² or Z⁴ when R³ is hydrogen;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen;

-   -   alkyl;    -   alkenyl;    -   hydroxyalkyl;    -   haloalkyl;    -   mercaptoalkyl;    -   aminoalkyl;    -   alkylaminoalkyl;    -   dialkylaminoalkyl;    -   alkoxyalkyl;    -   aminocarbonylalkyl;    -   cycloalkyl; and    -   phenyl optionally substituted with one or more substituents        independently selected from the group consisting of alkyl,        cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino,        hydroxy, nitro, haloalkyl, and alkoxy; or

R⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl,hydroxyalkyl, haloalkyl, mercaptoalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, alkoxyalkyl, aminocarbonylalkyl, cycloalkyl, andphenyl optionally substituted with one or more substituentsindependently selected from the group consisting of alkyl, cycloalkyl,halogen, cyano, amino, alkylamino, dialkylamino, hydroxy, nitro,haloalkyl, and alkoxy, and

R⁵ is selected from the group consisting of

-   -   hydroxyalkyl optionally substituted at one or more carbon atoms        with optionally substituted aryl or optionally substituted        benzyl;    -   aminoalkyl;    -   dialkylaminoalkyl;    -   diaminoalkyl;    -   alkoxyalkyl;    -   aminocarbonylalkyl;    -   cycloalkyl;    -   alkyl optionally substituted with one or two substituents each        independently selected from the group consisting of optionally        substituted cycloalkyl, optionally substituted phenyl,        optionally substituted benzyl, optionally substituted benzyloxy,        optionally substituted heteroaryl, and optionally substituted        heterocyclo;    -   optionally substituted heteroaryl;    -   R¹⁶—C(O)—; and    -   R¹⁶—SO₂—, wherein

R¹⁶ is selected from the group consisting of alkyl, alkoxy, optionallysubstituted cycloalkyl, optionally substituted aryl, optionallysubstituted benzyl, and 1,2,3,4-tetrahydroquinolinyl or1,2,3,4-tetrahydroisoquinolinyl optionally substituted at the nitrogenatom with alkylcarbonyl or haloalkylcarbonyl; or

R⁴ and R⁵ together with the nitrogen atom to which they are attachedform a 5- or 6-membered heterocyclic ring wherein one or more carbonatoms of the heterocyclic ring are optionally replaced with NR¹⁷, O, orS, wherein R¹⁷ is hydrogen or C₁₋₃ alkyl;

R⁶ and R⁷ are each independently selected from the group consisting ofhydrogen;

-   -   alkyl;    -   alkenyl;    -   alkynyl;    -   hydroxyalkyl;    -   alkoxyalkyl;    -   haloalkyl;    -   aminoalkyl;    -   cycloalkyl, wherein one or more carbon atoms are optionally        replaced with NR¹⁷, O, S, or SO₂, wherein R¹⁷ is hydrogen or        C₁₋₃ alkyl, to form a heterocyclic ring;    -   bicycloalkyl;    -   cycloalkylalkyl, wherein one or more carbon atoms of the        cycloalkyl ring are optionally replaced with NR¹⁷, O, S, or SO₂,        wherein R¹⁷ is hydrogen or C₁₋₃ alkyl, to form a heterocyclic        ring;    -   phenyl optionally substituted with one or two substituents        independently selected from the group consisting of alkyl,        cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino,        hydroxy, nitro, haloalkyl, and alkoxy;    -   benzyl optionally substituted with one or two substituents        independently selected from the group consisting of alkyl,        cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino,        hydroxy, nitro, haloalkyl, and alkoxy;    -   benzyloxyalkyl;    -   benzyloxybenzyl;    -   naphthylmethyl;    -   heteroaryl optionally substituted with one or two substituents        independently selected from the group consisting of alkyl,        cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino,        hydroxy, nitro, haloalkyl, and alkoxy; and    -   heteroarylalkyl optionally substituted with one or two        substituents independently selected from the group consisting of        alkyl, cycloalkyl, halogen, cyano, amino, alkylamino,        dialkylamino, hydroxy, nitro, haloalkyl, and alkoxy;

provided that when either R⁴ or R⁵ is cycloalkyl and y is 0, then atleast one of R⁶ and R⁷ is other than hydrogen; or

R⁶ and R⁷ together form benzylidenyl optionally substituted with one ortwo substituents independently selected from the group consisting ofalkyl, cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino,hydroxy, nitro, haloalkyl, and alkoxy; or

R⁶ and R⁷ together with the carbon atom to which they are attached forma saturated or unsaturated C₃₋₇ cycloalkyl ring optionally substitutedwith one or more substituents each independently selected from the groupconsisting of hydroxy, amino, carboxy, alkoxycarbonyl, alkylamino,dialkylamino, and ═O, wherein one or more carbon atoms of the C₃₋₇cycloalkyl ring are optionally replaced with NR¹⁷, O, S, or SO₂, whereinR¹⁷ is hydrogen or C₁₋₃ alkyl, to form a heterocyclic ring; or whereintwo adjacent carbon atoms of the C₃₋₇ cycloalkyl ring form a bridge —O—to form a bicyclic ring; or wherein one carbon atom of the C₃₋₇cycloalkyl ring is linked to a heterocyclic ring to form a spirocyclicring; or

R⁷ is hydrogen; R⁴ is hydrogen, alkyl or hydroxyalkyl; and R⁵ and R⁶together form a bridge —CH₂—CH₂—CH₂— or —CH₂—CHG¹-CHG²-CH₂—, wherein G¹and G² are both hydrogen or together with the carbon atoms to which theyare attached form a fused phenyl group;

R³² and R³³ are each independently selected from the group consisting ofhydroxy, alkyl, hydroxyalkyl, haloalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, and alkoxyalkyl; or

R³³ is hydrogen and R³² is as defined above; or

R³² and R³³ together with the carbon atom to which they are attachedform a C₃₋₇ cycloalkyl ring; or

R³² and R⁴ together with the carbon and nitrogen atoms to which they areattached, respectively, form a 4-, 5- or 6-membered heterocyclic ringoptionally substituted with one or more substituents each independentlyselected from the group consisting of hydroxy, hydroxyalkyl, alkyl,amino, alkylamino, dialkylamino, carboxy, and alkoxycarbonyl; R³³ ishydrogen, hydroxy, alkyl, hydroxyalkyl, haloalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, or alkoxyalkyl; and R⁵, R⁶, and R⁷are each independently selected from hydrogen, alkyl, hydroxyalkyl,alkoxyalkyl, haloalkyl, aminoalkyl, carboxy, and alkoxycarbonyl;

R⁸ and R⁹ are both hydrogen or together form ═O;

R¹⁰, R¹¹, R¹² and R¹³ are each independently selected from the groupconsisting of hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxy,hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino;

R¹⁴ is selected from the group consisting of

-   -   phenyl optionally substituted with one or two substituents        independently selected from the group consisting of alkyl,        alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino,        aminoalkyl, alkylamino, and dialkylamino;    -   naphthyl optionally substituted with one or two substituents        independently selected from the group consisting of alkyl,        alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino,        aminoalkyl, alkylamino, and dialkylamino;    -   quinolinyl;    -   pyridyl;    -   phenyl substituted with phenyl, benzyl, phenoxy, or benzyloxy,        wherein each phenyl ring is optionally substituted with one or        two substituents independently selected from the group        consisting of halogen, haloalkyl, alkyl, alkoxy, hydroxy, amino,        and cyano;    -   alkyl optionally substituted with hydroxy; and    -   —NR^(14a)R^(14b), wherein R^(14a) and R^(14b) are each        independently selected from the group consisting of        -   hydrogen;        -   alkyl;        -   aryl optionally substituted with one or more substituents            each independently selected from the group consisting of            alkyl,    -   alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino,        aminoalkyl, alkylamino, dialkylamino, alkoxycarbonyl, and        haloalkoxy;        -   benzyl optionally substituted with one or more substituents            each independently selected from the group consisting of            alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl,            cyano, amino, aminoalkyl, alkylamino, dialkylamino,            alkoxycarbonyl, and haloalkoxy;        -   heteroaryl optionally substituted with one or more            substituents each independently selected from the group            consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy,            hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino,            dialkylamino, alkoxycarbonyl, and haloalkoxy; and            heteroarylalkyl optionally substituted with one or more            substituents each independently selected from the group            consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy,            hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino,            dialkylamino, alkoxycarbonyl, and haloalkoxy;

R¹⁵ is selected from the group consisting of

-   -   phenyl or naphthyl, either of which is optionally substituted        with one or two substituents independently selected from the        group consisting of alkyl, alkoxy, halogen, haloalkyl, amino,        alkylamino and dialkylamino; and    -   alkyl substituted with one or two substituents each        independently selected from the group consisting of optionally        substituted cycloalkyl, optionally substituted aryl, optionally        substituted arylalkyl, optionally substituted heteroaryl, and        optionally substituted heterocyclo;

R³⁰ and R³¹ are each independently selected from the group consisting of

-   -   alkyl optionally substituted with one or two substituents        independently selected from the group consisting of optionally        substituted cycloalkyl, optionally substituted phenyl,        optionally substituted benzyl, optionally substituted        heteroaryl, and optionally substituted heterocyclo;    -   hydroxyalkyl optionally substituted at one or more carbon atoms        with optionally substituted aryl or optionally substituted        benzyl;    -   aminoalkyl;    -   dialkylaminoalkyl;    -   diaminoalkyl;    -   alkoxyalkyl;    -   optionally substituted cycloalkyl;    -   optionally substituted phenyl;    -   optionally substituted benzyl;    -   optionally substituted heteroaryl; and    -   optionally substituted heterocyclo;

A is O, —C(O)—, CH₂, or absent (a covalent bond), and B is CH or N, or

A-B is CH═C;

D is —C(O)—, —CH═CH—, —NH—, —N(alkyl)-, or absent (a covalent bond);

x is 0 or 1;

y is 0 or 1;

m is 0, 1, 2, or 3;

n is 0, 1, 2, 3, 4, or 5;

p is 0, 1, 2, 3, or 4; and

q is 0, 1, 2, or 3.

In compounds of Formula I where Z is Z¹, the carbon to which the —NR⁴R⁵group is attached can be a chiral center. The carbon at the 3-positionof the azetidine, pyrrolidine, piperidine, and hexahydroazepine ring,i.e., the carbon where the benzenesulfonamide group is attached, canalso be a chiral center. Accordingly, the configuration at those carbonatoms can be (R) or (S).

The groups R¹⁰-R¹³, when they are not equal to H, each take the place ofa hydrogen atom that would otherwise be present in any position on thephenyl ring to which the particular R group is attached. Similarly,optional substituents attached to aryl, phenyl, and heteroaryl ringseach take the place of a hydrogen atom that would otherwise be presentin any position on the aryl or heteroaryl rings.

One group of compounds useful in this aspect of the present inventionare compounds of Formula I as defined above, but with the followingprovisos:

1) when Z is Z¹, q is 1, m and y are 0, R³ is cyclohexyl, R⁴-R⁶ are eachhydrogen, and R⁷ is benzyl substituted with chlorine at thepara-position, then R¹ and R² are not both hydrogen;

2) when Z is Z³, q is 1, D is absent, R⁸ and R⁹ are both hydrogen, and

p is 0, then R¹⁴ is not an unsubstituted phenyl;

3) when Z is Z⁵, q is 0, and R³⁰ and R³¹ are both optionally substitutedphenyl, then R³ is not alkyl; or

4) when Z is Z¹, q is 1, m and y are 0, R³ is cyclohexyl, R⁴ and R⁶ areeach hydrogen, R⁵ is alkoxycarbonyl, and R⁷ is benzyl substituted withchlorine at the para-position, then R¹ and R² are not both hydrogen.

In one aspect, compounds useful in the present invention are compoundsof Formula I:

and pharmaceutically acceptable salts, prodrugs and solvate thereof,wherein:

R¹ and R² are each independently selected from the group consisting ofhydrogen, alkyl, haloalkyl, halogen, alkoxy, haloalkoxy, cyano, nitro,amino, aminoalkyl, alkylamino, dialkylamino, and hydroxy;

R³ is selected from the group consisting of alkyl, alkenyl, cycloalkyl,cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydrofuranylalkyl, 3-tetrahydrofuranylalkyl,alkylsulfonylaminoalkyl, and aminocarbonylalkyl;

Z is selected from the group consisting of Z¹, Z², Z³, Z⁴, and Z⁵,wherein

Z¹ is

Z² is

Z³ is—CR⁸R⁹—(CH₂)_(p)-D-R¹⁴;Z⁴ is—SO₂—R¹⁵; andZ⁵ is

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen;

-   -   alkyl;    -   alkenyl;    -   hydroxyalkyl;    -   haloalkyl;    -   mercaptoalkyl;    -   aminoalkyl;    -   alkylaminoalkyl;    -   dialkylaminoalkyl;    -   alkoxyalkyl; and    -   phenyl optionally substituted with one or more substituents        independently selected from the group consisting of alkyl,        cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino,        hydroxy, nitro, haloalkyl, and alkoxy; or

R⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl,hydroxyalkyl, haloalkyl, mercaptoalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, alkoxyalkyl, and phenyl optionally substituted withone or more substituents independently selected from the groupconsisting of alkyl, cycloalkyl, halogen, cyano, amino, alkylamino,dialkylamino, hydroxy, nitro, haloalkyl, and alkoxy, and R⁵ is selectedfrom the group consisting of

-   -   hydroxyalkyl optionally substituted at one or more carbon atoms        with optionally substituted aryl or optionally substituted        benzyl;    -   aminoalkyl;    -   dialkylaminoalkyl;    -   diaminoalkyl;    -   alkoxyalkyl;    -   alkyl optionally substituted with one or two substituents each        independently selected from the group consisting of optionally        substituted cycloalkyl, optionally substituted phenyl,        optionally substituted benzyl, optionally substituted        heteroaryl, and optionally substituted heterocyclo;    -   R¹⁶—C(O)—; and    -   R¹⁶—SO₂—, wherein

R¹⁶ is selected from the group consisting of alkyl, optionallysubstituted cycloalkyl, optionally substituted aryl, optionallysubstituted benzyl, and 1,2,3,4-tetrahydroquinolinyl or1,2,3,4-tetrahydroisoquinolinyl optionally substituted at the nitrogenatom with alkylcarbonyl or haloalkylcarbonyl; or

R⁴ and R⁵ together with the nitrogen atom to which they are attachedform a 5- or 6-membered heterocyclic ring wherein one or more carbonatoms of the heterocyclic ring are optionally replaced with NR¹⁷, O, orS,

wherein R¹⁷ is hydrogen or C₁₋₃ alkyl;

R⁶ and R⁷ are each independently selected from the group consisting ofhydrogen;

-   -   alkyl;    -   hydroxyalkyl;    -   alkoxyalkyl;    -   haloalkyl;    -   aminoalkyl;    -   cycloalkyl;    -   phenyl optionally substituted with one or two substituents        independently selected from the group consisting of alkyl,        cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino,        hydroxy, nitro, haloalkyl, and alkoxy;    -   benzyl optionally substituted with one or two substituents        independently selected from the group consisting of alkyl,        cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino,        hydroxy, nitro, haloalkyl, and alkoxy; and    -   benzyloxyalkyl; or

R⁶ and R⁷ together with the carbon atom to which they are attached forma C₃₋₇ cycloalkyl ring optionally substituted with one or moresubstituents each independently selected from the group consisting ofhydroxy, amino, carboxy, alkoxycarbonyl, alkylamino, dialkylamino, and═O, wherein one or more carbon atoms of the C₃₋₇ cycloalkyl ring areoptionally replaced with NR¹⁷ or O, wherein R¹⁷ is hydrogen or C₁₋₃alkyl, to form a heterocyclic ring; or wherein two adjacent carbon atomsof the C₃₋₇ cycloalkyl ring can form a bridge —O— to form a bicyclicring; or wherein one carbon atom of the C₃₋₇ cycloalkyl ring is linkedto a heterocyclic ring to form a spirocyclic ring;

R⁷ is hydrogen, R⁴ is hydrogen or alkyl, and R⁵ and R⁶ together form abridge —CH₂—CH₂—CH₂— or —CH₂—CHG¹-CHG²-CH₂—, wherein G¹ and G² are bothhydrogen or together with the carbon atoms to which they are attachedform a fused phenyl group;

R⁸ and R⁹ are both hydrogen or together form ═O;

R¹⁰, R¹¹, R¹² and R¹³ are each independently selected from the groupconsisting of hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxy,hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino;

R¹⁴ is selected from the group consisting of

-   -   phenyl optionally substituted with one or two substituents        independently selected from the group consisting of alkyl,        alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino,        aminoalkyl, alkylamino, and dialkylamino;    -   naphthyl optionally substituted with one or two substituents        independently selected from the group consisting of alkyl,        alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino,        aminoalkyl, alkylamino, and dialkylamino;    -   quinolinyl;    -   pyridyl;    -   phenyl substituted with phenyl, benzyl, phenoxy, or benzyloxy,        wherein each phenyl ring is optionally substituted with one or        two substituents independently selected from the group        consisting of halogen, haloalkyl, alkyl, alkoxy, hydroxy, amino        and cyano; alkyl; and    -   —NR^(14a)R^(14b), wherein R^(14a) and R^(14b) are each        independently selected from the group consisting of    -   hydrogen;    -   alkyl;    -   aryl optionally substituted with one or more substituents each        independently selected from the group consisting of alkyl,        alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino,        aminoalkyl, alkylamino, and dialkylamino; and    -   benzyl optionally substituted with one or more substituents each        independently selected from the group consisting of alkyl,        alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino,        aminoalkyl, alkylamino, and dialkylamino;

R¹⁵ is phenyl or naphthyl, either of which is optionally substitutedwith one or two substituents independently selected from the groupconsisting of alkyl, alkoxy, halogen, haloalkyl, amino, alkylamino anddialkylamino;

R³⁰ and R³¹ are each independently selected from the group consisting of

-   -   alkyl optionally substituted with one or two substituents        independently selected from the group consisting of optionally        substituted cycloalkyl, optionally substituted phenyl,        optionally substituted benzyl, optionally substituted        heteroaryl, and optionally substituted heterocyclo;    -   hydroxyalkyl optionally substituted at one or more carbon atoms        with optionally substituted aryl or optionally substituted        benzyl;    -   aminoalkyl;    -   dialkylaminoalkyl;    -   diaminoalkyl;    -   alkoxyalkyl;    -   optionally substituted cycloalkyl;    -   optionally substituted phenyl;    -   optionally substituted benzyl;    -   optionally substituted heteroaryl; and    -   optionally substituted heterocyclo;

A is O, —C(O)—, CH₂, or absent, and B is CH or N; or

A-B is CH═C;

D is —C(O)—, —CH═CH—, —NH—, —N(alkyl)-, or absent, provided that D isother than —NH— or —N(alkyl)-when R¹⁴ is —NR^(14a)R^(14b);

m is 0, 1, 2 or 3;

n is 0, 1, 2, 3, 4, or 5;

p is 0, 1, 2, 3, or 4; and

q is 0, 1, 2, or 3;

with the proviso that when Z is Z¹, q and m are 0, R³ is cyclohexyl,R⁴-R⁶ are each hydrogen, and R⁷ is phenyl substituted with chlorine atthe para-position, then R¹ and R² are not both hydrogen.

In one embodiment, compounds useful in the present invention arecompounds represented by Formula II:

and pharmaceutically acceptable salts, prodrugs, and solvates thereof,wherein R¹, R², Z, and q are as defined above.

In one aspect, preferred compounds falling within the scope of FormulaII include those represented by Formula III:

and pharmaceutically acceptable salts, prodrugs, and solvates thereof,wherein Z and q are as defined above.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III where q is 0 (azetidinyl).

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III where q is 1 (pyrrolidinyl).

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III where q is 2 (piperidinyl).

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III where q is 3 (hexahydroazepinyl).

Preferably, in compounds of Formulae I and II, R¹ and R² are eachindependently selected from the group consisting of hydrogen, halogen,alkyl, haloalkyl, cyano, alkoxy, haloalkoxy, amino, alkylamino,dialkylamino, and nitro. More preferably, R¹ and R² are eachindependently selected from the group consisting of hydrogen, halogen,C₁₋₆ alkyl, halo(C₁₋₆)alkyl, cyano, C₁₋₆ alkoxy, halo(C₁₋₆)alkoxy,amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, and nitro; and morepreferably independently selected from the group consisting of hydrogen,halogen, C₁₋₃ alkyl, halo(C₁₋₃)alkyl, cyano, C₁₋₃ alkoxy,halo(C₁₋₃)alkoxy, and nitro. Advantageously, R¹ and R² are independentlyhydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl,difluoromethyl, fluoromethyl, cyano, nitro, methoxy or difluoromethoxy.More preferably, R¹ is hydrogen and R² is trifluoromethyl, or both R¹and R² are hydrogen. Preferably, R² is in the meta-position of thephenyl ring.

In one embodiment, compounds useful in the present invention are thosewhere R³ is alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl,hydroxyalkyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl,2-tetrahydrofuranylalkyl, 3-tetrahydrofuranylalkyl,alkylsulfonylaminoalkyl, aminocarbonylalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, cyanoalkyl, carboxyalkyl, oralkoxycarbonylalkyl. Preferably, R³ is selected from the groupconsisting of alkyl, cycloalkyl, cycloalkylalkyl, 3-tetrahydrofuranyl,2-tetrahydrofuranylalkyl, alkoxyalkyl, hydroxyalkyl,alkylsulfonylaminoalkyl and aminocarbonylalkyl; more preferably selectedfrom C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-tetrahydrofuranyl,2-tetrahydrofuranyl(C₁₋₃)alkyl, C₃₋₆ cycloalkyl(C₁₋₃)alkyl, C₁₋₃alkoxy(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, C₁₋₃alkylsulfonylamino(C₁₋₃)alkyl, and aminocarbonyl(C₁₋₃)alkyl.Advantageously, R³ is selected from the group consisting of methyl,ethyl, iso-pentyl, iso-butyl, iso-propyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclopropylmethyl, cyclopropylethyl, methoxymethyl,methoxyethyl, hydroxymethyl, hydroxyethyl, 3-tetrahydrofuranyl,2-tetrahydrofuranylmethyl, 2-tetrahydrofuranylethyl,methylsulfonamidomethyl, methylsulfonamidoethyl, aminocarbonylmethyl,and aminocarbonylethyl. More advantageously, R³ is cyclopropyl, methyl,iso-propyl, or iso-butyl, especially cyclopropyl.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein Z is Z¹, and R⁴ and R⁵ areeach independently selected from the group consisting of

-   -   hydrogen;    -   alkyl;    -   alkenyl;    -   hydroxyalkyl;    -   haloalkyl;    -   mercaptoalkyl;    -   aminoalkyl;    -   alkylaminoalkyl;    -   dialkylaminoalkyl;    -   alkoxyalkyl;    -   aminocarbonylalkyl;    -   cycloalkyl; and    -   phenyl optionally substituted with one or more substituents        independently selected from the group consisting of alkyl,        cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino,        hydroxy, nitro, haloalkyl, and alkoxy,

provided that when either R⁴ or R⁵ is cycloalkyl and y is 0, then atleast one of R⁶ and R⁷ is other than hydrogen.

Useful compounds include those where R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen, alkyl, hydroxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl,unsubstituted phenyl, and phenyl substituted with one or twosubstituents independently selected from the group consisting of alkyl,cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino, hydroxy,nitro, haloalkyl, and alkoxy; more preferably independently selectedfrom hydrogen, C₁₋₆ alkyl, hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, C₁₋₆alkylamino(C₁₋₆)alkyl, di(C₁₋₆)alkylamino(C₁₋₆)alkyl, unsubstitutedphenyl, and phenyl substituted with one or two substituentsindependently selected from the group consisting of alkyl, cycloalkyl,halogen, cyano, amino, alkylamino, dialkylamino, hydroxy, nitro,haloalkyl, and alkoxy; more preferably independently selected fromhydrogen, C₁₋₃ alkyl, hydroxy(C₁₋₃)alkyl, unsubstituted phenyl, andphenyl optionally substituted with one or two substituents independentlyselected from the group consisting of alkyl, cycloalkyl, halogen, cyano,amino, alkylamino, dialkylamino, hydroxy, nitro, haloalkyl, and alkoxy;and more preferably independently selected from hydrogen, methyl, ethyl,propyl, isopropyl, isobutyl, isopentyl, hydroxymethyl, hydroxyethyl, andunsubstituted phenyl; or R⁴ and R⁵ together with the nitrogen atom towhich they are attached form a 5- or 6-membered heterocyclic ringselected from the group consisting of oxazolidinyl, isoxazolidinyl,pyrrolidinyl, pyrazolidinyl, imidazolidinyl, hexahydropyrimidinyl,piperidinyl, piperazinyl, 4-methylpiperazinyl, morpholinyl,thiomorpholinyl, and tetrahydropyridyl. Advantageously, R⁴ and R⁵ areindependently hydrogen, methyl or hydroxyethyl, or R⁴ and R⁵ togetherwith the nitrogen atom to which they are attached form 1-pyrrolidinyl,4-thiomorpholinyl, piperazinyl, or 4-methylpiperazinyl.

In one embodiment, useful compounds in the present invention arecompounds of any of Formulae I-III, wherein R⁴ is selected from thegroup consisting of hydrogen, alkyl, alkenyl, hydroxyalkyl, haloalkyl,mercaptoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,alkoxyalkyl, aminocarbonylalkyl, cycloalkyl, and phenyl optionallysubstituted with one or more substituents, preferably one or twosubstituents, independently selected from the group consisting of alkyl,cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino, hydroxy,nitro, haloalkyl, and alkoxy, and R⁵ is selected from the groupconsisting of

-   -   hydroxyalkyl optionally substituted at one or more carbon atoms        with optionally substituted aryl or optionally substituted        benzyl;    -   aminoalkyl;    -   dialkylaminoalkyl;    -   diaminoalkyl;    -   alkoxyalkyl;    -   aminocarbonylalkyl;    -   cycloalkyl;    -   alkyl optionally substituted with one or two substituents each        independently selected from the group consisting of optionally        substituted cycloalkyl, optionally substituted phenyl,        optionally substituted benzyl, optionally substituted benzyloxy,        optionally substituted heteroaryl, and optionally substituted        heterocyclo; and    -   optionally substituted heteroaryl,

provided that when either R⁴ or R⁵ is cycloalkyl and y is 0, then atleast one of R⁶ and R⁷ is other than hydrogen.

Useful hydroxyalkyl groups for R⁵ optionally substituted at one or morecarbon atoms with an optionally substituted aryl or an optionallysubstituted benzyl include, for example, hydroxymethyl, 1-hydroxyethyl,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxybutyl,2-hydroxy-1-methylpropyl, 2-hydroxy-2-phenylethyl,2-benzyl-2-hydroxyethyl, 2-hydroxy-1-phenylethyl,1-benzyl-2-hydroxyethyl, and 2-hydroxy-1-phenylpropyl.

Useful alkyl groups for R⁵ optionally substituted with one or twosubstituents each independently selected from the group consisting ofoptionally substituted cycloalkyl, optionally substituted phenyl,optionally substituted benzyl, optionally substituted benzyloxy,optionally substituted heteroaryl, and optionally substitutedheterocyclo include, for example, C₁₋₆ alkyl optionally substituted withoptionally substituted cycloalkyl, optionally substituted phenyl,optionally substituted benzyl, optionally substituted heteroaryl, oroptionally substituted heterocyclo, such as methyl, ethyl, propyl,isopropyl, 1-methylpropyl, C₁₋₃ alkyl substituted at the 1-position withoptionally substituted cycloalkyl, optionally substituted phenyl,optionally substituted benzyl, optionally substituted heteroaryl, suchas 2-pyridylmethyl, 3-pyridylmethyl, 2-thienylmethyl, 2-furanylethyl,4-imidazolylethyl and 1-imidazolylpropyl, or optionally substitutedheterocyclo. Useful substituted alkyl groups for R⁵ include C₁₋₃ alkylsubstituted with unsubstituted cycloalkyl; unsubstituted phenyl; phenylsubstituted with one or two substituents selected from the groupconsisting of alkyl, alkoxy, alkoxycarbonyl, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylaminoand dialkylamino; unsubstituted benzyl; unsubstituted benzyloxy;unsubstituted heteroaryl; or unsubstituted heterocyclo.

Useful optionally substituted heteroaryl groups for R⁵ include 1-, 2-,or 3-pyridyl, 2-pyrazinyl, and 3-isoxazolyl.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, where R⁵ is R¹⁶—C(O)— wherein R¹⁶ isas defined above. Useful compounds include those where R¹⁶ is alkyl,cycloalkyl, or phenyl unsubstituted or substituted with one or twosubstituents independently selected from the group consisting of alkyl,alkoxy, halogen, haloalkyl, haloalkoxy, amino, alkylamino, anddialkylamino.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, where R⁵ is R¹⁶—SO₂— where R¹⁶ is asdefined above. Useful compounds include those where R¹⁶ is alkyl,especially methyl; phenyl unsubstituted or substituted with one or twosubstituents independently selected from the group consisting of alkyl,alkoxy, halogen, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino,and alkylcarbonylamino; or 1,2,3,4-tetrahydroquinolinyl or1,2,3,4-tetrahydroisoquinolinyl optionally substituted at the nitrogenatom with alkylcarbonyl or haloalkylcarbonyl.

In another embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, where R⁵ is selected from the groupconsisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, and alkoxyalkyl. Useful compounds include those whereR⁵ is, for example, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxybutyl, or2-hydroxy-1-methylpropyl.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein Z is Z¹ and R⁶ and R⁷ areeach independently selected from the group consisting of

-   -   hydrogen;    -   alkyl;    -   hydroxyalkyl;    -   alkoxyalkyl;    -   haloalkyl;    -   aminoalkyl;    -   cycloalkyl;    -   phenyl optionally substituted with one or two substituents        independently selected from the group consisting of alkyl,        cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino,        hydroxy, nitro, haloalkyl, and alkoxy;    -   benzyl optionally substituted with one or two substituents        independently selected from the group consisting of alkyl,        cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino,        hydroxy, nitro, haloalkyl, and alkoxy;    -   benzyloxyalkyl;    -   heteroaryl optionally substituted with one or two substituents        independently selected from the group consisting of alkyl,        cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino,        hydroxy, nitro, haloalkyl, and alkoxy; and    -   heteroarylalkyl optionally substituted with one or two        substituents independently selected from the group consisting of        alkyl, cycloalkyl, halogen, cyano, amino, alkylamino,        dialkylamino, hydroxy, nitro, haloalkyl, and alkoxy.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein Z is Z¹, and R⁶ is hydrogenand R⁷ is selected from the group consisting of

-   -   hydrogen;    -   alkyl;    -   alkenyl;    -   alkynyl;    -   hydroxyalkyl;    -   alkoxyalkyl;    -   haloalkyl;    -   aminoalkyl;    -   cycloalkyl, wherein one or more carbon atoms are optionally        replaced with NR¹⁷, O, S, or SO₂, wherein R¹⁷ is hydrogen or        C₁₋₃ alkyl, to form a heterocyclic ring;    -   bicycloalkyl;    -   cycloalkylalkyl, wherein one or more carbon atoms of the        cycloalkyl ring are optionally replaced with NR¹⁷, O, S, or SO₂,        wherein R¹⁷ is hydrogen or C₁₋₃ alkyl, to form a heterocyclic        ring;    -   phenyl optionally substituted with one or two substituents        independently selected from the group consisting of alkyl,        cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino,        hydroxy, nitro, haloalkyl, and alkoxy;    -   benzyl optionally substituted with one or two substituents        independently selected from the group consisting of alkyl,        cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino,        hydroxy, nitro, haloalkyl, and alkoxy;    -   benzyloxyalkyl;    -   benzyloxybenzyl;    -   naphthylmethyl;    -   heteroaryl optionally substituted with one or two substituents        independently selected from the group consisting of alkyl,        cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino,        hydroxy, nitro, haloalkyl, and alkoxy; and    -   heteroarylalkyl optionally substituted with one or two        substituents independently selected from the group consisting of        alkyl, cycloalkyl, halogen, cyano, amino, alkylamino,        dialkylamino, hydroxy, nitro, haloalkyl, and alkoxy.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein Z is Z¹, and R⁶ is hydrogenand R⁷ is selected from the group consisting of

-   -   hydrogen;    -   alkyl;    -   hydroxyalkyl;    -   alkoxyalkyl;    -   haloalkyl;    -   aminoalkyl;    -   cycloalkyl;    -   phenyl optionally substituted with one or two substituents        independently selected from the group consisting of alkyl,        cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino,        hydroxy, nitro, haloalkyl, and alkoxy;    -   benzyl optionally substituted with one or two substituents        independently selected from the group consisting of alkyl,        cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino,        hydroxy, nitro, haloalkyl, and alkoxy;    -   benzyloxyalkyl;    -   heteroaryl optionally substituted with one or two substituents        independently selected from the group consisting of alkyl,        cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino,        hydroxy, nitro, haloalkyl, and alkoxy; and    -   heteroarylalkyl optionally substituted with one or two        substituents independently selected from the group consisting of        alkyl, cycloalkyl, halogen, cyano, amino, alkylamino,        dialkylamino, hydroxy, nitro, haloalkyl, and alkoxy.

When R⁶ is hydrogen, R⁷ is preferably selected from the group consistingof alkyl; hydroxyalkyl; cycloalkyl; phenyl optionally substituted withone or two substituents independently selected from the group consistingof alkyl, cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino,hydroxy, nitro, haloalkyl, and alkoxy; benzyl optionally substitutedwith one or two substituents independently selected from the groupconsisting of alkyl, cycloalkyl, halogen, cyano, amino, alkylamino,dialkylamino, hydroxy, nitro, haloalkyl, and alkoxy; and benzyloxyalkyl.More preferably, R⁷ is selected from the group consisting of straightchain C₁₋₆ alkyl; branched chain C₃₋₆ alkyl; hydroxy(C₁₋₆)alkyl; C₃₋₆cycloalkyl; unsubstituted phenyl; phenyl substituted with one or twosubstituents independently selected from the group consisting of C₁₋₆alkyl, C₃₋₆ cycloalkyl, halogen, cyano, amino, C₁₋₃ alkylamino,di(C₁₋₃)alkylamino, hydroxy, nitro, halo(C₁₋₆)alkyl, and C₁₋₆ alkoxy;unsubstituted benzyl; benzyl substituted with one or two substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₃₋₆cycloalkyl, halogen, cyano, amino, C₁₋₃ alkylamino, di(C₁₋₃)alkylamino,hydroxy, nitro, halo(C₁₋₆)alkyl, and C₁₋₆ alkoxy; andbenzyloxy(C₁₋₃)alkyl. Advantageously, R⁷ is methyl; propyl; iso-propyl;butyl; tert-butyl; sec-butyl; iso-butyl; hydroxymethyl; 1-hydroxyethyl;unsubstituted phenyl; phenyl substituted with one or two substituentsindependently selected from the group consisting of methyl ethyl,propyl, iso-propyl, butyl, tert-butyl, halogen, cyano, amino,methylamino, dimethylamino, hydroxy, nitro, and trifluoromethyl;unsubstituted benzyl; benzyl substituted with one or two substituentsindependently selected from the group consisting of methyl ethyl,propyl, iso-propyl, butyl, tert-butyl, halogen, cyano, amino,methylamino, dimethylamino, hydroxy, nitro, and trifluoromethyl;1-benzyloxyethyl; cyclopentyl; cyclohexyl; cyclopentylmethyl; orcyclohexylmethyl.

In one preferred aspect, when R⁶ is hydrogen and R⁷ is alkyl, R⁴ and R⁵together form a 5- or 6-membered heterocycle as described above, or R⁴and R⁵ are independently hydrogen, alkyl, or hydroxyalkyl.

In one embodiment, useful compounds of the present invention arecompounds of any of Formulae I-III, wherein R⁶ and R⁷ together formbenzylidenyl optionally substituted with one or two substituentsindependently selected from the group consisting of alkyl, cycloalkyl,halogen, cyano, amino, alkylamino, dialkylamino, hydroxy, nitro,haloalkyl, and alkoxy.

In one embodiment, useful compounds of the present invention arecompounds of any of Formulae I-III, wherein R⁶ and R⁷ together with thecarbon atom to which they are attached form a saturated or unsaturatedC₃₋₇ cycloalkyl ring optionally substituted with one or moresubstituents each independently selected from the group consisting ofhydroxy, amino, carboxy, alkoxycarbonyl, alkylamino, dialkylamino, and═O, wherein one or more carbon atoms of the C₃₋₇ cycloalkyl ring areoptionally replaced with NR¹⁷, O, S, or SO₂, wherein R¹⁷ is hydrogen orC₁₋₃ alkyl, to form a heterocyclic ring; or wherein two adjacent carbonatoms of the C₃₋₇ cycloalkyl ring form a bridge —O— to form a bicyclicring; or wherein one carbon atom of the C₃₋₇ cycloalkyl ring is linkedto a heterocyclic ring to form a spirocyclic ring.

In one embodiment, useful compounds of the present invention arecompounds of any of Formulae I-III, wherein R⁶ and R⁷ together with thecarbon atom to which they are attached form a saturated C₃₋₇ cycloalkylring optionally substituted with one or more, preferably one or two,substituents each independently selected from the group consisting ofhydroxy, amino, carboxy, alkoxycarbonyl, alkylamino, dialkylamino, and═O. Useful compounds include those where R⁶ and R⁷ together with thecarbon atom to which they are attached form a C₃₋₆ cycloalkyl ring,which is preferably cyclopentyl or cyclohexyl.

In one embodiment, useful compounds of the present invention arecompounds of any of Formulae I-III, wherein R⁶ and R⁷ together with thecarbon atom to which they are attached form a saturated C₃₋₇ cycloalkylring where one or more carbon atoms are replaced with NR¹⁷, O, S, orSO₂, preferably replaced with NR¹⁷ or O, wherein R¹⁷ is hydrogen or C₁₋₃alkyl, to form a heterocyclic ring which can be optionally substitutedwith one or more, preferably one or two, substituents each independentlyselected from the group consisting of hydroxy, amino, carboxy,alkoxycarbonyl, alkylamino, dialkylamino, and ═O. Examples of suchheterocyclic groups include pyrrolidinyl, tetrahydrofuranyl,tetrahydropyranyl, and piperidinyl.

In one embodiment, compounds of the present invention are compounds ofany of Formulae I-III, wherein R⁶ and R⁷ together with the carbon atomto which they are attached form a saturated C₃₋₇ cycloalkyl ring,wherein two adjacent carbon atoms of the cycloalkyl ring form a bridge—O—to form a bicyclic ring, such as 6-oxa-bicyclo[3.1.0]hexane.

In one embodiment, compounds of the present invention are compounds ofany of Formulae I-III, wherein R⁶ and R⁷ together with the carbon atomto which they are attached form a saturated C₃₋₇ cycloalkyl ring,wherein one carbon atom is linked to a heterocyclic ring to form aspirocyclic ring, such as 1,4-dioxa-spiro[4.5]decane.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein R⁷ is hydrogen; R⁴ ishydrogen, alkyl, or hydroxyalkyl; and R⁵ and R⁶ together form a bridge—CH₂—CH₂—CH₂— or —CH₂—CHG¹-CHG²-CH₂—, wherein G¹ and G² are bothhydrogen or together with the carbon atoms to which they are attachedform a fused phenyl group. Useful compounds include those where R⁷ ishydrogen, R⁴ is hydrogen, methyl or ethyl, and R⁵ and R⁶ together form abridge —CH₂—CH₂—CH₂— or —CH₂—CHG¹-CHG²-CH₂—, wherein G¹ and G² are bothhydrogen or together with the carbon atoms to which they are attachedform a fused phenyl group. Advantageously, R⁵ and R⁶ together form—CH₂—CH₂—CH₂—.

In one embodiment, useful compounds of the present invention arecompounds of any of Formulae I-III where Z is Z¹ and x, y, and m areeach 0 (zero).

In one embodiment, useful compounds of the present invention arecompounds of any of Formulae I-III where Z is Z¹, m is 1, and x and yare each 0.

In one embodiment, useful compounds of the present invention arecompounds of any of Formulae I-III where Z is Z¹ and x is 0.

In one embodiment, useful compounds of the present invention arecompounds of any of Formulae I-III where Z is Z¹ and x is 1.

In one embodiment, useful compounds of the present invention arecompounds of any of Formulae I-III where Z is Z¹ and y is 0.

In one embodiment, useful compounds of the present invention arecompounds of any of Formulae I-III where Z is Z¹ and y is 1.

In one embodiment, useful compounds of the present invention arecompounds of any of Formulae I-III where y is 1 and R³² and R³³ are eachindependently selected from the group consisting of hydroxy, alkyl,hydroxyalkyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,and alkoxyalkyl; or R³³ is hydrogen and R³² is as defined above. Usefulcompounds include those where R³² is hydroxy or alkyl, such as C₁₋₃alkyl, and R³³ is hydrogen. Useful compounds also include those whereR³² and

R³³ are both alkyl, such as C₁₋₃ alkyl, and preferably methyl.

In one embodiment, useful compounds of the present invention arecompounds of any of Formulae I-III, wherein y is 1 and R³² and R³³together with the carbon atom to which they are attached form a C₃₋₇cycloalkyl ring, preferably cyclopropyl, cyclopentyl, and cyclohexyl.

In one embodiment, useful compounds of the present invention arecompounds of any of Formulae I-III, wherein y is 1 and R³² and R⁴together with the carbon and nitrogen atoms to which they are attached,respectively, form a 4-membered heterocyclic ring optionally substitutedwith one or more, preferably one or two, substituents each independentlyselected from the group consisting of hydroxy, hydroxyalkyl, alkyl,amino, alkylamino, dialkylamino, carboxy, and alkoxycarbonyl; R³³ ishydrogen, hydroxy, alkyl, hydroxyalkyl, haloalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, or alkoxyalkyl; and R⁵, R⁶ and R⁷are each independently selected from the group consisting of hydrogen,alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aminoalkyl, carboxy, andalkoxycarbonyl. Preferably the 4-membered heterocyclic ring isunsubstituted, and R⁵, R⁶ and R⁷ are each hydrogen.

In one embodiment, useful compounds of the present invention arecompounds of any of Formulae I-III, wherein y is 1 and R³² and R⁴together with the carbon and nitrogen atoms to which they are attached,respectively, form a 5- or 6-membered heterocyclic ring optionallysubstituted with one or more, preferably one or two, substituents eachindependently selected from the group consisting of hydroxy,hydroxyalkyl, alkyl, amino, alkylamino, dialkylamino, carboxy, andalkoxycarbonyl; R³³ is hydrogen, hydroxy, alkyl, hydroxyalkyl,haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, oralkoxyalkyl; and R⁵, R⁶ and R⁷ are each independently selected from thegroup consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,haloalkyl, aminoalkyl, carboxy, and alkoxycarbonyl. Useful compoundsinclude those, where x is 0 or 1, m is 0, 1, 2, or 3, R³³ is hydrogen oralkyl, R⁶ is hydrogen and R⁷ is hydrogen, alkyl, preferably C₁₋₃ alkyl,carboxy or alkoxycarbonyl, preferably C₁₋₄ alkoxycarbonyl, and R⁵ ishydrogen, alkyl, hydroxyalkyl, preferably C₁₋₃ hydroxyalkyl, oralkoxycarbonyl, preferably C₁₋₄ alkoxycarbonyl.

Suitable heterocyclic rings formed by R³² and R⁴ include 2-piperidinyl,1-hydroxyethyl-2-piperidinyl, 3-piperidinyl,1-tert-butoxycarbonyl-2-carboxy-3-piperidinyl, 4-piperidinyl,1-tert-butoxycarbonyl-2-carboxy-4-piperidinyl, 2-pyrrolidinyl,1-hydroxyethyl-2-pyrrolidinyl, 3-pyrrolidinyl,2-carboxy-4-isopropyl-3-pyrrolidinyl, 3-methyl-3-pyrrolidinyl, and4,4-dimethyl-3-pyrrolidinyl.

Useful compounds include those where R⁸ and R⁹ are both hydrogen when Zis Z², A is CH₂ or absent and B is CH. Other useful compounds includethose where R⁸ and R⁹ form ═O when Z is Z², A is CH₂ or absent and B isCH, or A-B is CH═C. Additional useful compounds include those where Z isZ², R⁸ and R⁹ are both hydrogen and A is O.

Useful compounds include those where R⁸ and R⁹ are both hydrogen when Zis Z², A is —C(O)— and B is N.

Useful compounds include those where Z is Z², R⁸ and R⁹ together form═O, A is CH₂ or absent and B is N.

Preferably, R¹⁰, R¹¹, R¹², and R¹³ are each independently selected fromthe group consisting of hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,halogen, halo(C₁₋₆)alkyl, hydroxy, hydroxy(C₁₋₆)alkyl, cyano, amino,amino(C₁₋₆)alkyl, C₁₋₃ alkylamino, and di(C₁₋₃)alkylamino. Morepreferably, R¹⁰, R¹¹, R¹², and R¹³ are each independently selected fromthe group consisting of hydrogen, halogen, C₁₋₄ alkyl, C₁₋₃ alkoxy,halo, halo(C₁₋₃)alkyl, cyano, amino, amino (C₁₋₃)alkyl, C₁₋₃ alkylamino,and di(C₁₋₃)alkylamino. Advantageously, R¹⁰, R¹¹, R¹², and R¹³ are eachindependently selected from the group consisting of hydrogen, halogen,methyl, ethyl, methoxy, ethoxy, trifluoromethyl, cyano, amino,methylamino, and dimethylamino, and especially halogen. Preferably, R¹⁰and R¹² are both hydrogen. Preferably, either or both R¹¹ and R¹³ are atthe para-position of their respective phenyl rings.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein Z is Z³ and R¹⁴ is selectedfrom the group consisting of

-   -   phenyl optionally substituted with one or two substituents        independently selected from the group consisting of alkyl,        alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino,        aminoalkyl, alkylamino, and dialkylamino;    -   naphthyl optionally substituted with one or two substituents        independently selected from the group consisting of alkyl,        alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino,        aminoalkyl, alkylamino, and dialkylamino;    -   quinolinyl;    -   pyridyl;    -   phenyl substituted with phenyl, benzyl, phenoxy, or benzyloxy,        wherein each phenyl ring is optionally substituted with one or        two substituents independently selected from the group        consisting of halogen, haloalkyl, alkyl, alkoxy, hydroxy, amino,        and cyano;    -   alkyl optionally substituted with hydroxy; and    -   —NR^(14a)R^(14b), wherein R^(14a) and R^(14b) are each        independently selected from the group consisting of hydrogen;        alkyl; aryl optionally substituted with one or more substituents        each independently selected from the group consisting of alkyl,        alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino,        aminoalkyl, alkylamino, dialkylamino, alkoxycarbonyl, and        haloalkoxy; benzyl optionally substituted with one or more        substituents each independently selected from the group        consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy,        hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino,        dialkylamino, alkoxycarbonyl, and haloalkoxy; heteroaryl        optionally substituted with one or more substituents each        independently selected from the group consisting of alkyl,        alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino,        aminoalkyl, alkylamino, dialkylamino, alkoxycarbonyl, and        haloalkoxy; and heteroarylalkyl optionally substituted with one        or more substituents each independently selected from the group        consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy,        hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino,        dialkylamino, alkoxycarbonyl, and haloalkoxy.

Useful compounds include those where R¹⁴ is selected from the groupconsisting of phenyl optionally substituted with one or two substituentsindependently selected from the group consisting of alkyl, alkoxy,halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl,alkylamino, and dialkylamino; phenyl substituted with phenyl, benzyl,phenoxy or benzyloxy, wherein each phenyl ring is optionally substitutedwith one or two substituents selected from the group consisting ofhalogen, haloalkyl, alkyl, alkoxy, hydroxy, amino, and cyano; naphthyl;quinolinyl; and pyridyl.

Useful compounds include those where R¹⁴ is phenyl optionallysubstituted with one or two substituents independently selected from thegroup consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy,hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino;preferably independently selected from the group consisting of alkyl,alkoxy, halo, haloalkyl, hydroxy, cyano, alkylamino, and dialkylamino;and more preferably independently selected from the group consisting ofC₁₋₆ alkyl, C₁₋₆ alkoxy, halo, halo(C₁₋₃)alkyl, hydroxy, cyano, C₁₋₃alkylamino, and di(C₁₋₃)alkylamino. Advantageously, R¹⁴ is a phenylgroup substituted with one or two substituents independently selectedfrom the group consisting of methyl, ethyl, iso-propyl, tert-butyl,methoxy, ethoxy, fluoro, trifluoromethyl, methylamino, anddimethylamino.

Useful compounds include those where R¹⁴ is phenyl substituted,preferably at the para-position, with phenyl, benzyl, phenoxy orbenzyloxy any of which are unsubstituted or substituted with halogen,haloalkyl, alkyl, alkoxy, hydroxy, amino, or cyano, and preferablysubstituted with halogen.

Useful compounds also include those where R¹⁴ is unsubstituted naphthyl,quinolinyl or pyridyl.

Useful compounds include those where R¹⁴ is —NR^(14a)R¹⁴b, whereinR^(14a) and R^(14b) are each independently selected from the groupconsisting of hydrogen; alkyl; aryl optionally substituted with one ormore, preferably one or two, substituents each independently selectedfrom the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy,hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, dialkylamino,alkoxycarbonyl, and haloalkoxy; benzyl optionally substituted with oneor more, preferably one or two, substituents each independently selectedfrom the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy,hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, dialkylamino,alkoxycarbonyl, and haloalkoxy; heteroaryl optionally substituted withone or more, preferably one or two, substituents each independentlyselected from the group consisting of alkyl, alkoxy, halogen, haloalkyl,hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino,dialkylamino, alkoxycarbonyl, and haloalkoxy; and heteroarylalkyloptionally substituted with one or more, preferably one or two,substituents each independently selected from the group consisting ofalkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino,aminoalkyl, alkylamino, dialkylamino, alkoxycarbonyl, and haloalkoxy.

Preferably, R⁸ and R⁹ are both hydrogen when R¹⁴ is one of

-   -   naphthyl;    -   quinolinyl;    -   pyridyl;    -   phenyl substituted with phenyl optionally substituted with        halogen, haloalkyl, alkyl, alkoxy, hydroxy, amino, or cyano;    -   phenyl substituted with benzyl optionally substituted with        halogen, haloalkyl, alkyl, alkoxy, hydroxy, amino, or cyano;    -   phenyl substituted with phenoxy optionally substituted with        halogen, haloalkyl, alkyl, alkoxy, hydroxy, amino, or cyano; or    -   phenyl substituted with benzyloxy optionally substituted with        halogen, haloalkyl, alkyl, alkoxy, hydroxy, amino, or cyano.

Useful compounds also include those where Z is Z³, R⁸ and R⁹ togetherform ═O, p is 0, D is —CH═CH— and R¹⁴ is n-propyl.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein R¹⁴ is alkyl optionallysubstituted with hydroxy. Useful compounds include those where R⁸ and R⁹together form ═O, D is absent, and R¹⁴ is alkyl substituted withhydroxy, such as 1-hydroxybutyl, 1-hydroxy-3-methylbutyl, and1-hydroxy-2-methylbutyl.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein R¹⁵ is phenyl or naphthyl,either of which is optionally substituted with one or two substituentsindependently selected from the group consisting of alkyl, alkoxy,halogen, haloalkyl, amino, alkylamino and dialkylamino. In thisembodiment, R¹⁵ is preferably phenyl substituted with one or twosubstituents independently selected from the group consisting of alkyl,alkoxy, halogen, haloalkyl, amino, alkylamino and dialkylamino. Usefulcompounds include those where R¹⁵ is phenyl substituted with C₁₋₆ alkyl,C₁₋₆ alkoxy, halogen, halo(C₁₋₃)alkyl, amino, C₁₋₃ alkylamino ordi(C₁₋₃)alkylamino; and more preferably substituted with propyl, butyl,pentyl, propoxy, butoxy, pentoxy, fluoro, chloro, trifluoromethyl,amino, methylamino or dimethylamino. Useful compounds also include thosewhere R¹⁵ is naphthyl substituted with amino, alkylamino ordialkylamino; preferably substituted with amino, C₁₋₃ alkylamino ordi(C₁₋₃)alkylamino; and more preferably substituted with amino,methylamino or dimethylamino.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein R¹⁵ is alkyl substitutedwith one or two substituents each independently selected from the groupconsisting of optionally substituted cycloalkyl, optionally substitutedaryl, optionally substituted arylalkyl, optionally substitutedheteroaryl, and optionally substituted heterocyclo. Useful compoundsinclude those where R¹⁵ is C₁₋₆ alkyl substituted with one or twosubstituents selected from the group of optionally substituted phenyl,optionally substituted naphthyl, and optionally substituted pyridyl.

Useful compounds include those where R⁸ and R⁹ are both hydrogen ortogether form ═O and D is absent or —CH═CH—. Useful compounds includethose where R⁸ and R⁹ form ═O and D is —C(O)—.

Useful compounds include those where D is —C(O)— or absent and R¹⁴ is—NR^(14a)R^(14b).

Useful compounds include also those where D is —NH— or —N(alkyl)-.

Useful compounds of the present invention include those where Z is Z⁵and R³⁰ and R³¹ are each independently selected from the groupconsisting of alkyl, such as C₁₋₄ alkyl, hydroxy(C₁₋₄)alkyl,amino(C₁₋₄)alkyl, di(C₁₋₄)alkylamino(C₁₋₄)alkyl, diamino(C₁₋₄)alkyl,(C₁₋₄)alkoxy(C₁₋₄)alkyl, C₃₋₇ cycloalkyl, phenyl, benzyl, and pyridyl,such as 2-, 3-, or 4-pyridyl, wherein the cycloalkyl, phenyl, benzyl andpyridyl rings can be optionally substituted.

Useful compounds of the present invention include those where m is 0 or1.

Preferably, Z is Z² and n is 0, 1 or 2.

Preferably, Z is Z³ and p is 0, 1 or 2.

Preferably, q is 2.

The invention also relates to compounds represented by Formula IV:

and pharmaceutically acceptable salts, prodrugs and solvates thereof,wherein R¹-R⁷, R³², R³³, x, y, m, and q are as defined above. Preferredvalues for R¹-R⁷, R³², R³³, x, y, m, and q are those described above aspreferred for Formula I.

The invention also relates to compounds represented by Formula V:

and pharmaceutically acceptable salts, prodrugs and solvates thereof,wherein R¹-R⁷, m and q are as defined above. Preferred values for R¹-R⁷,m, and q are those described above as preferred for Formula I.

In one aspect, preferred compounds falling within the scope of Formula Vinclude those represented by Formula VI:

and pharmaceutically acceptable salts, prodrugs, and solvates thereof,wherein:

R¹-R³ and q are as described for Formula V;

R⁴¹ and R⁵¹ are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, hydroxyalkyl, haloalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, and alkoxyalkyl; and

R¹⁸ and R¹⁹ are each independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, halogen, cyano, amino, alkylamino,dialkylamino, hydroxy, nitro, haloalkyl, and alkoxy.

Preferably, R⁴¹ and R⁵¹ are each independently selected from the groupconsisting of hydrogen, alkyl, and hydroxyalkyl; and more preferablyindependently selected from hydrogen and alkyl. Useful compounds includethose where R⁴¹ and R⁵¹ both are hydrogen, or R⁴¹ is hydrogen and R⁵¹ isC₁₋₃ alkyl, preferably methyl.

Preferably, R¹⁸ and R¹⁹ are each independently selected from the groupconsisting of hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, halogen, cyano,amino, C₁₋₃ alkylamino, di(C₁₋₃)alkylamino, hydroxy, nitro,halo(C₁₋₆)alkyl, and C₁₋₆ alkoxy; more preferably independently selectedfrom the group consisting of hydrogen, C₁₋₄ alkyl, halogen, cyano,amino, C₁₋₃ alkylamino, di(C₁₋₃)alkylamino, hydroxy, nitro,halo(C₁₋₃)alkyl, and C₁₋₄ alkoxy; and more preferably independentlyselected from the group consisting of hydrogen, methyl, iso-propyl,tert-butyl, cyano, fluoro, amino, methylamino, dimethylamino, nitro,trifluoromethyl, methoxy, iso-propoxy, and tert-butoxy. Useful compoundsof Formula VI include those where R¹⁸ and R¹⁹ are both hydrogen, or R¹⁸is hydrogen and R¹⁹ is methyl, tert-butyl, cyano, fluoro, methylamino,dimethylamino, trifluoromethyl or methoxy, and especially cyano.

In another aspect, preferred compounds falling within the scope ofFormula V include those represented by Formula VII:

and pharmaceutically acceptable salts, prodrugs, and solvates thereof,wherein:

R¹-R³, m, and q are as defined above for Formula I;

R⁴² and R⁵² are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, hydroxyalkyl, haloalkyl, mercaptoalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, and alkoxyalkyl; or R⁴²and R⁵² together with the nitrogen atom to which they are attached forma 5- or a 6-membered heterocyclic ring wherein one or more carbon atomsof the heterocyclic ring are optionally replaced with NR¹⁷, O or S,wherein R¹⁷ is hydrogen or C₁₋₃ alkyl; and

R²⁰ and R²¹ are independently H or CH₃.

Preferred values for R¹-R³ and q are those described for Formula I.Preferably, R⁴² and R⁵² are each independently selected from the groupconsisting of hydrogen, alkyl, hydroxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, and alkoxyalkyl; more preferablyselected from hydrogen, C₁₋₆ alkyl, and hydroxy(C₁₋₆)alkyl; morepreferably independently selected from hydrogen, C₁₋₃ alkyl, andhydroxy(C₁₋₃)alkyl; and more preferably independently selected fromhydrogen, methyl, ethyl, hydroxymethyl and hydroxyethyl; or R⁴² and R⁵²together with the nitrogen atom to which they are attached form a 5- or6-membered heterocyclic ring selected from the group consisting ofoxazolidinyl, isoxazolidinyl, pyrrolidinyl, pyrazolidinyl,imidazolidinyl, hexahydropyrimidinyl, piperidinyl, piperazinyl,4-methylpiperazinyl, morpholinyl, thiomorpholinyl, andtetrahydropyridyl. Advantageously, R⁴² and R⁵² are independentlyhydrogen, methyl or hydroxyethyl; or R⁴² and R⁵² together with thenitrogen atom to which they are attached form 1-pyrrolidinyl,4-thiomorpholinyl, or 4-methylpiperazinyl.

Useful compounds of Formula VII include those where one of R²⁰ or R²¹ isCH₃. Other useful compounds of Formula VII include those where R²⁰ andR²¹ are both H when R⁴² and R⁵² together form a 5- or 6-memberedheterocyclic ring. Also, useful compounds of Formula VII include thosewhere R⁴² and R⁵² are both hydrogen, or R⁴² is hydrogen and R⁵² isalkyl, and especially methyl. Preferably, m is 1 in compounds of FormulaVII.

In one aspect, compounds falling within the scope of Formula IV includethose represented by Formula VIII:

and pharmaceutically acceptable salts, prodrugs and solvates thereof,wherein R¹—-R⁷, R³², R³³, and q are as defined above. Preferred valuesfor R¹-R⁷, R³², R³³, and q are those described above as preferred forFormula I.

Useful compounds of Formula VIII include those where R³³ is hydrogen.Useful compounds of Formula VIII also include those where R³² is hydroxyor alkyl or R³² and R³³ together form a C₃₋₆ cycloalkyl. Usefulcompounds of Formula VIII also include those where R³² and R⁴ togetherform a 5-membered heterocyclic ring.

In one aspect, compounds falling within the scope of Formula IV includethose represented by Formula IX:

and pharmaceutically acceptable salts, prodrugs and solvates thereof,wherein R¹-R⁷, R³², R³³, m and q are as defined above. Preferred valuesfor R¹-R⁷, R³², R³³, m, and q are those described above as preferred forFormula I.

Useful compounds of Formula IX include those where R³² and R³³ togetherform C₅₋₆ cycloalkyl, R⁶ and R⁷ are hydrogen, m is 0, and R¹-R⁵ are asdefined above. Another group of useful compounds are those where R³³ ishydrogen, R³² is hydroxy and m is 0, and R¹-R⁷ are as defined above.

Another group of compounds useful in this aspect of the invention arecompounds represented by the general Formula X:

and pharmaceutically acceptable salts, prodrugs and solvates thereof,wherein:

R¹-R³, R⁸-R¹³, A, B, q, and n are as defined above for Formulae I-III.Preferred values for R¹-R³, R⁸-R¹³, A, B, n, and q are those describedabove as preferred for Formula I.

Further, compounds useful in the present invention are compounds ofFormula XI:

and pharmaceutically acceptable salts, prodrugs and solvates thereof,wherein:

R¹-R³, R⁸, R⁹, R¹⁴, D, p, and q are as defined previously for Formula I.In Formula XI, preferred values for R¹-R³, R⁸, R⁹, R¹⁴, D, p and q arethose described above as preferred for Formula I.

Additional compounds useful in the present invention are compoundsrepresented by Formula XII:

and pharmaceutically acceptable salts, prodrugs and solvates thereof,wherein:

R¹-R³, R¹⁵ and q are as defined previously for Formula I. In FormulaXII, preferred values for R¹-R³, R¹⁵ and q are those described above aspreferred for Formula I.

Additional compounds useful in the present invention are compoundsrepresented by Formula XIII:

and pharmaceutically acceptable salts, prodrugs and solvates thereof,wherein:

R¹-R³, R³⁰, R³¹, and q are as defined previously for Formula I. InFormula XIII, preferred values for R¹-R³, R³⁰, R³¹ and q are thosedescribed above as preferred for Formula I.

Exemplary preferred compounds useful in the present invention include:

-   N-[1-(2-amino-4-methylpentanoyl)piperidin-3-yl]-N-cyclopropyl-3-trifluoromethylbenzenesulfonamide;-   N-cyclopropyl-N-[1-(4-methyl-2-methylaminopentanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;-   N-cyclopropyl-N-[1-(2-ethylamino-4-methylpentanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;-   N-[1-(3-amino-5-methylhexanoyl)piperidin-3-yl]-N-cyclopropyl-3-trifluoromethylbenzenesulfonamide;-   N-cyclopropyl-N-[1-(2-methylcarbonylpropylamino-4-methyl-pentanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;-   N-cyclopropyl-N-{1-[2-(3-methylbutyl)amino-4-methylpentanoyl]piperidin-3-yl}-3-trifluoromethylbenzenesulfonamide;-   N-cyclopropyl-N-[1-(2-isopropylamino-4-methylpentanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;-   N-cyclopropyl-N-[1-(3-methylamino-5-methylhexanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;    and pharmaceutically acceptable salts, prodrugs and solvates    thereof.

Another group of useful compounds of the invention include:

-   (2S)N-[1-(2-amino-4-methylpentanoyl)piperidin-3-yl]-N-cyclopropyl-3-trifluoromethylbenzenesulfonamide;-   (2S)N-cyclopropyl-N-[1-(4-methyl-2-methylaminopentanoyl)-piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;-   (2S)N-cyclopropyl-N-[1-(2-ethylamino-4-methylpentanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;-   5    (2S)N-[1-(3-amino-5-methylhexanoyl)piperidin-3-yl]-N-cyclopropyl-3-trifluoromethylbenzenesulfonamide;-   (2S)N-cyclopropyl-N-[1-(2-methylcarbonylpropylamino-4-methyl-pentanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;-   (2S)N-cyclopropyl-N-{1-[2-(3-methylbutyl)amino-4-methyl-pentanoyl]piperidin-3-yl}-3-trifluoromethylbenzenesulfonamide;-   (2S)N-cyclopropyl-N-[1-(2-isopropylamino-4-methylpentanoyl)-piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;-   (2S)N-cyclopropyl-N-[1-(3-methylamino-5-methylhexanoyl)-piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;-   (2R)    N-cyclopropyl-N-[1-(3-methylamino-5-methylhexanoyl)-piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;    and pharmaceutically acceptable salts, prodrugs and solvates    thereof.

Another group of useful compounds of the invention include:

-   N-cyclopropyl-N-(1-{3-[bis-(4-fluorophenyl)amino]propyl}-piperidin-3-yl)-3-trifluoromethylbenzenesulfonamide;-   N-cyclopropyl-N-[1-(3-isobutylaminopropionyl)-piperidin-3-yl]-3-trifluoromethyl-benzenesulfonamide;-   N-cyclopropyl-N-[1-(3-isopropylaminopropionyl)-piperidin-3-yl]-3-trifluoromethyl-benzenesulfonamide;-   N-cyclopropyl-N-{1-[3-(2-methoxyethylamino)-propionyl]-piperidin-3-yl}-3-trifluoromethyl-benzenesulfonamide;-   N-cyclopropyl-N-{1-[3-(2-hydroxyethylamino)-propionyl]-piperidin-3-yl}-3-trifluoromethyl-benzenesulfonamide;-   N-cyclopropyl-N-[1-(2-isobutylaminoacetyl)-piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;-   2-{3-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)-amino]-piperidin-1-yl}-N-isobutyl-acetamide;-   N-(4-fluorophenyl)-2-{3-[cyclopropyl-(3-trifluoromethylbenzene-sulfonyl)amino]piperidin-1-yl}acetamide;-   2-[3-trifluoromethylbenzenesulfonamino)-pyrrolidin-1-yl]-N-(4-fluorophenyl)-acetamide;-   N-cyclopropyl-N-{1-[2-(4-methoxybenzylamino)acetyl]-piperidin-3-yl}-3-trifluoromethylbenzenesulfonamide;-   N-cyclopropyl-N-(1-{2-[(pyridin-3-ylmethyl)amino]acetyl}-piperidin-3-yl)-3-trifluoromethylbenzenesulfonamide;    and pharmaceutically acceptable salts, prodrugs and solvates    thereof.

Useful cycloalkyl groups are selected from saturated C₃₋₁₂ cycloalkyl.Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl.

As used herein, the term “bicycloalkyl” refers to saturated alicyclichydrocarbon systems consisting of two rings and having two or more atomsin common. Useful bicycloalkyl groups are selected from C₄₋₁₂bicycloalkyl. Typical bicycloalkyl groups include bicyclobutyl,bicyclopentyl, bicyclohexyl, bicycloheptyl, and bicyclooctyl, especiallybicyclo[3.1.0]hept-3-yl.

Useful halo or halogen groups include fluorine, chlorine, bromine andiodine.

Useful alkyl groups are selected from straight-chained and branchedC₁₋₁₀ alkyl groups, more preferably straight chain C₁₋₆ alkyl groups andbranched chain C₁₋₆ alkyl groups. Typical C₁₋₁₀ alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl,iso-butyl, 3-pentyl, hexyl and octyl, among others.

Useful alkenyl groups are selected from C₂₋₆ alkenyl groups, preferablyC₂₋₄ alkenyl. Typical C₂₋₄ alkenyl groups include ethenyl, propenyl,2-propenyl, isopropenyl, butenyl, 2-butenyl, 3-butenyl, and sec-butenyl.

Useful alkynyl groups are selected from C₂₋₆ alkynyl groups, preferablyC₂₋₄ alkynyl. Typical C₂₋₄ alkynyl groups include ethynyl, propynyl,2-propynyl, butynyl, 2-butynyl, and 3-butynyl groups.

Useful arylalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted by any of the C₆₋₁₄ aryl groups mentioned below.Typical arylalkyl groups include benzyl, phenethyl, and naphthylmethyl.

Useful arylalkenyl groups include any of the above-mentioned C₂₋₆alkenyl groups substituted by any of the C₆₋₁₄ aryl groups mentionedbelow.

Useful arylalkynyl groups include any of the above-mentioned C₂₋₆alkynyl groups substituted by any of the C₆₋₁₄ aryl groups mentionedbelow.

As used herein, the term “benzylidenyl” refers to ═CHPh.

As used herein, the term “benzyloxybenzyl” refers to a benzyl groupsubstituted by a benzyloxy group at the phenyl ring of the benzyl group.

Useful benzyloxybenzyl groups include 4-(benzyloxy)benzyl.

Useful cycloalkylalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by any of the above-mentioned cycloalkylgroups.

Useful haloalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted by one or more fluorine, chlorine, bromine or iodineatoms (e.g., fluoromethyl, difluoromethyl, trifluoromethyl,pentafluoroethyl, 1,1-difluoroethyl and trichloromethyl groups).

Useful hydroxyalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by hydroxy (e.g., hydroxymethyl, hydroxyethyl,hydroxypropyl and hydroxybutyl groups, and especially hydroxymethyl,1-hydroxyethyl, 2-hydroxypropyl, 3-hydroxybutyl, and2-hydroxy-1-methylpropyl).

Useful alkoxy groups include oxygen substituted by one of the C₁₋₁₀alkyl groups mentioned above.

Useful alkoxyalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted with any of the above-mentioned alkoxy groups.

Useful haloalkoxy groups include oxygen substituted by one of the C₁₋₁₀haloalkyl groups mentioned above (e.g., fluoromethoxy, difluoromethoxy,and trifluoromethoxy).

Useful aryl groups are C₆₋₁₄ aryl, especially C₆₋₁₀ aryl. Typical C₆₋₁₄aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl,azulenyl, biphenyl, biphenylenyl, and fluorenyl groups, more preferablyphenyl, naphthyl, and biphenyl groups.

The term “heteroaryl” as employed herein refers to groups having 5 to 14ring atoms, with 6, 10 or 14π electrons shared in a cyclic array, andcontaining carbon atoms and 1, 2, or 3 oxygen, nitrogen or sulfurheteroatoms. Examples of heteroaryl groups include thienyl,benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl,pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl,2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl,purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl,cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl,furazanyl, and phenoxazinyl. Preferred heteroaryl groups includethienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl,thiazolyl, isothiazolyl, and isoxazolyl.

Useful heteroarylalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by any of the heteroaryl groups mentionedbelow. Useful values include, for example, 2-pyridylmethyl,3-pyridylmethyl, 4-pyridylmethyl.

The terms “heterocyclic” and “heterocyclo” are used herein to meansaturated or wholly or partially unsaturated 3-7 membered monocyclic, or7-10 membered bicyclic ring system, which consist of carbon atoms andfrom one to four heteroatoms independently selected from the groupconsisting of O, N, and S, wherein the nitrogen and sulfur heteroatomscan be optionally oxidized, the nitrogen can be optionally quaternized,and including any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring, and wherein theheterocyclic ring can be substituted on a carbon atom or on a nitrogenatom if the resulting compound is stable. Examples include, but are notlimited to, pyrrolidine, piperidine, piperazine, morpholine,imidazoline, pyrazolidine, benzodiazepines, and the like.

Useful heterocycloalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by any of the above-mentioned heterocyclicgroups.

As used herein, the term “amino” or “amino group” refers to —NH₂.

Useful aminoalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted with an amino group.

Useful diaminoalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted with two amino groups.

Useful alkylamino and dialkylamino groups are —NHR²² and —NR²²R²³,respectively, wherein R²² and R²³ are each independently selected from aC₁₋₁₀ alkyl group.

Useful alkylaminoalkyl and dialkylaminoalkyl groups are any of theabove-mentioned C₁₋₁₀ alkyl groups substituted by any of theabove-mentioned alkylamino and dialkylamino groups, respectively.

Useful alkylsulfonylaminoalkyl groups include any of the above-mentionedC₁₋₁₀ alkyl groups substituted by an alkyl-SO₂—NH— group.

Useful aminocarbonylalkyl groups include any of the above-mentionedC₁₋₁₀ alkyl groups substituted with an aminocarbonyl group, i.e.,—C(O)NH₂.

Useful alkylcarbonyl groups include a carbonyl group, i.e., —C(O)—,substituted by any of the above-mentioned C₁₋₁₀ alkyl groups. Usefulhaloalkylcarbonyl groups include a carbonyl group substituted by any ofthe above-mentioned haloalkyl groups.

Useful alkylcarbonylamino groups include any of the above-mentionedalkylcarbonyl groups attached to an amino nitrogen, such asmethylcarbonylamino.

Useful mercaptoalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by a —SH group.

As used herein, the term “carboxy” refers to —COOH.

Useful carboxyalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by —COOH.

As used herein, the term “ureido” refers to —NH—C(O)—NH₂.

As used herein, the term “azido” refers to —N₃.

As used herein, the term “optionally substituted” refers to a group thatcan be unsubstituted or substituted.

Optional substituents on optionally substituted groups, when nototherwise indicated, include one or more groups, preferably 1, 2, or 3groups, independently selected from the group consisting of halo,halo(C₁₋₆)alkyl, aryl, heterocycle, cycloalkyl, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl(C₁₋₆)alkyl, aryl(C₂₋₆)alkenyl,aryl(C₂₋₆)alkynyl, cycloalkyl(C₁₋₆)alkyl, heterocyclo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, carboxy(C₁₋₆)alkyl,alkoxy(C₁₋₆)alkyl, nitro, amino, ureido, cyano, alkylcarbonylamino,hydroxy, thiol, alkylcarbonyloxy, azido, alkoxy, carboxy, aminocarbonyl,and C₁₋₆ alkylthiol groups mentioned above. Preferred optionalsubstituents include halo, halo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl,amino(C₁₋₆)alkyl, hydroxy, nitro, C₁₋₆ alkyl, alkoxy, and amino.

The invention disclosed herein is also intended to encompass prodrugs ofany of the disclosed compounds. As used herein, prodrugs are consideredto be any covalently bonded carriers that release the active parent drugin vivo. Non-limiting examples of prodrugs include esters or amides ofcompounds of any of Formulae I-XIII having hydroxyalkyl or aminoalkyl asa substituent, and these may be prepared by reacting such compounds withanhydrides such as succinic anhydride.

The invention disclosed herein is also intended to encompass any of thedisclosed compounds being isotopically-labelled by having one or moreatoms replaced by an atom having a different atomic mass or mass number.Examples of isotopes that can be incorporated into the disclosedcompounds include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N,¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively, and preferably ³H,¹¹C, and ¹⁴C. Isotopically-labeled compounds of the present inventioncan be prepared by methods known in the art.

The present invention is also directed specifically to ³H, ¹¹C, or ¹⁴Cradiolabeled compounds of any of Formulae I-XIII, as well as theirpharmaceutically acceptable salts, prodrugs and solvates, and the use ofany such compounds as radioligands for their binding site on the calciumchannel. For example, one use of the labeled compounds of the presentinvention is the characterization of specific receptor binding. Anotheruse of a labeled compound of the present invention is an alternative toanimal testing for the evaluation of structure-activity relationships.For example, the receptor assay may be performed at a fixedconcentration of a labeled compound of the invention and at increasingconcentrations of a test compound in a competition assay. For example, atritiated compound of any of Formulae I-XIII can be prepared byintroducing tritium into the particular compound, for example, bycatalytic dehalogenation with tritium. This method may include reactinga suitably halogen-substituted precursor of the compound with tritiumgas in the presence of a suitable catalyst, for example, Pd/C, in thepresence or absence of a base. Other suitable methods for preparingtritiated compounds can be found in Filer, Isotopes in the Physical andBiomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6(1987). ¹⁴C-labeled compounds can be prepared by employing startingmaterials having a ¹⁴C carbon. ¹¹C-labeled compounds can be prepared byemploying starting materials having a ¹¹C carbon.

Some of the compounds disclosed herein may contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms. The present invention is meant toencompass the uses of all such possible forms, as well as their racemicand resolved forms and mixtures thereof. The individual enantiomers maybe separated according to methods known to those of ordinary skill inthe art in view of the present disclosure. When the compounds describedherein contain olefinic double bonds or other centers of geometricasymmetry, and unless specified otherwise, it is intended that theyinclude both E and Z geometric isomers. All tautomers are intended to beencompassed by the present invention as well.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The terms “enantiomer” and “enantiomeric” refer to a molecule thatcannot be superimposed on its mirror image and hence is optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image compound rotates the plane of polarizedlight in the opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich mixture is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

The terms “a” and “an” refer to one or more.

The invention disclosed herein also encompasses the use of salts of thedisclosed compounds, including all non-toxic pharmaceutically acceptablesalts thereof of the disclosed compounds. Examples of pharmaceuticallyacceptable addition salts include inorganic and organic acid additionsalts and basic salts. The pharmaceutically acceptable salts include,but are not limited to, metal salts such as sodium salt, potassium salt,cesium salt and the like; alkaline earth metals such as calcium salt,magnesium salt and the like; organic amine salts such as triethylaminesalt, pyridine salt, picoline salt, ethanolamine salt, triethanolaminesalt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and thelike; inorganic acid salts such as hydrochloride, hydrobromide,phosphate, sulphate and the like; organic acid salts such as citrate,lactate, tartrate, maleate, fumarate, mandelate, acetate,dichloroacetate, trifluoroacetate, oxalate, formate and the like;sulfonates such as methanesulfonate, benzenesulfonate,p-toluenesulfonate and the like; and amino acid salts such as arginate,asparginate, glutamate and the like.

Acid addition salts can be formed by mixing a solution of the particularcompound of the present invention with a solution of a pharmaceuticallyacceptable non-toxic acid such as hydrochloric acid, fumaric acid,maleic acid, succinic acid, acetic acid, citric acid, tartaric acid,carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, or thelike. Basic salts can be formed by mixing a solution of the compound ofthe present invention with a solution of a pharmaceutically acceptablenon-toxic base such as sodium hydroxide, potassium hydroxide, cholinehydroxide, sodium carbonate and the like.

The invention disclosed herein is also meant to encompass solvates ofany of the disclosed compounds. One type of solvate is a hydrate.Solvates typically do not significantly alter the physiological activityor toxicity of the compounds, and as such may function aspharmacological equivalents.

Since compounds of Formulae I-XIII are blockers of calcium (Ca⁺)channels, a number of diseases and conditions mediated by calcium ioninflux can be treated by employing these compounds. The presentinvention is thus directed generally to a method for treating,preventing or ameliorating a disorder responsive to the blockade ofcalcium channels, and particularly the selective blockade of N-typecalcium channels, in an animal suffering from, or at risk of sufferingfrom, said disorder, said method comprising administering to the animalan effective amount of a compound represented by any of defined FormulaeI-XIII, or a pharmaceutically acceptable salt, prodrug or solvatethereof.

The present invention is further directed to a method of modulatingcalcium channels, especially N-type calcium channels, in an animal inneed thereof, said method comprising administering to the animal atleast one compound represented by any of defined Formulae I-XIII, or apharmaceutically acceptable salt, prodrug or solvate thereof. Morespecifically, the present invention provides a method of treating,preventing or ameliorating stroke, the neuronal damage resulting fromhead trauma, epilepsy, pain (e.g., chronic pain, neuropathic pain,inflammatory pain, or acute pain), migraine, a mood disorder,schizophrenia, a neurodegenerative disorder (e.g., Alzheimer's disease,amyotrophic lateral sclerosis (ALS), or Parkinson's disease),depression, anxiety, a psychosis, hypertension, or cardiac arrhythmia.In one embodiment, the invention provides a method of treating pain. Inanother embodiment, the type of pain treated is chronic pain. In anotherembodiment, the type of pain treated is neuropathic pain. In anotherembodiment, the type of pain treated is inflammatory pain. In anotherembodiment, the type of pain treated is acute pain. In each instance,such method of treatment, prevention, or amelioration requiresadministering to an animal in need of such treatment, prevention oramelioration an amount of a compound of the present invention that istherapeutically effective in achieving said treatment, prevention oramelioration. In one embodiment, the amount of such compound is theamount that is effective as to block calcium channels in vivo.

Chronic pain includes, but is not limited to, inflammatory pain,postoperative pain, cancer pain, osteoarthritis pain associated withmetastatic cancer, trigeminal neuralgia, acute herpetic and postherpeticneuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion,occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout,phantom limb pain, burn pain, and other forms of neuralgia, neuropathic,and idiopathic pain syndromes.

Chronic somatic pain generally results from inflammatory responses totissue injury such as nerve entrapment, surgical procedures, cancer orarthritis (Brower, Nature Biotechnology 2000; 18: 387-391).

The inflammatory process is a complex series of biochemical and cellularevents activated in response to tissue injury or the presence of foreignsubstances (Levine, Inflammatory Pain, In: Textbook of Pain, Wall andMelzack eds., 3^(rd) ed., 1994). Inflammation often occurs at the siteof injured tissue, or foreign material, and contributes to the processof tissue repair and healing. The cardinal signs of inflammation includeerythema (redness), heat, edema (swelling), pain and loss of function(ibid.). The majority of patients with inflammatory pain do notexperience pain continually, but rather experience enhanced pain whenthe inflamed site is moved or touched. Inflammatory pain includes, butis not limited to, that associated with osteoarthritis and rheumatoidarthritis.

Chronic neuropathic pain is a heterogenous disease state with an unclearetiology. In chronic neuropathic pain, the pain can be mediated bymultiple mechanisms. This type of pain generally arises from injury tothe peripheral or central nervous tissue. The syndromes include painassociated with spinal cord injury, multiple sclerosis, post-herpeticneuralgia, trigeminal neuralgia, phantom pain, causalgia, and reflexsympathetic dystrophy and lower back pain. Chronic pain is differentfrom acute pain in that patients suffer the abnormal pain sensationsthat can be described as spontaneous pain, continuous superficialburning and/or deep aching pain. The pain can be evoked by heat-, cold-,and mechano-hyperalgesia or by heat-, cold-, or mechano-allodynia.

Neuropathic pain can be caused by injury or infection of peripheralsensory nerves. It includes, but is not limited to, pain from peripheralnerve trauma, herpes virus infection, diabetes mellitus, causalgia,plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathicpain is also caused by nerve damage from chronic alcoholism, humanimmunodeficiency virus infection, hypothyroidism, uremia, or vitamindeficiences. Stroke (spinal or brain) and spinal cord injury can alsoinduce neuropathic pain. Cancer-related neuropathic pain results fromtumor growth compression of adjacent nerves, brain, or spinal cord. Inaddition, cancer treatments, including chemotherapy and radiationtherapy, can also cause nerve injury. Neuropathic pain includes but isnot limited to pain caused by nerve injury such as, for example, thepain from which diabetics suffer.

The present invention is also directed to the use of a compoundrepresented by any of defined Formulae I-XIII, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof, in the manufacture of amedicament for treating, preventing or ameliorating a disorderresponsive to the blockade of calcium channels (e.g., any of thedisorders listed above) in an animal suffering from said disorder. Inone embodiment, the disorder is responsive to the selective blockade ofN-type calcium channels.

The present invention is also directed to the use of a compoundrepresented by any of defined Formulae I-XIII, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof, in the manufacture of amedicament for modulating calcium channels, especially N-type calciumchannels, in an animal in need thereof.

Synthesis of Compounds

The compounds of the present invention can be prepared using methodsknown to those skilled in the art in view of this disclosure. Forexample, compounds of Formula I where Z is Z¹ can be prepared as shownin Schemes 1-5.

wherein R²⁴ is

In Scheme 1, R¹, R², and R³ are as defined above for Formula I. R⁶ andR⁷ are as defined above, or R⁶ and R⁷ together with the carbon atom towhich they are attached form a C₃₋₇ cyclolalkyl group.

Similarly, compounds of Formula I, where Z is Z¹, y is 1, and x is 0 or1 can be prepared according to Scheme 1 by choosing appropriate acids asstarting materials.

Compounds of Formula I where Z is Z¹ and m is 1 can be prepared asfollows:

where R³ and R⁷ are as defined for Formula I and R²⁴ is as describedabove in Scheme 1.

Compounds of Formula I where Z is Z¹ and m is 1 can also be preparedusing the Michael addition reaction of amines to α,β-unsaturated amidesas shown in Scheme 3:

where R³-R⁵, R⁷ and R²⁴ are as defined above.

Further compounds of Formula I where Z is Z¹ can be prepared as follows:

where R³, R⁴, R⁷ and R²⁴ are as defined above and R′ and R″ are eachindependently selected from the group consisting of hydrogen, alkyl,optionally substituted cycloalkyl, optionally substituted phenyl,optionally substituted benzyl, optionally substituted heteroaryl, andoptionally substituted heterocyclo.

A further method for preparing compounds of Formula I where Z is Z¹ canbe follows:

where R³-R⁵, R⁷, and R²⁴ are as defined above.

Compounds of Formula I where Z is Z², R⁸ and R⁹ are both hydrogen, A is—C(O)— and B is N can be prepared as shown in Scheme 6:

wherein R²⁵ is

In Scheme 6, R³ is as defined for Formula I and R²⁴ is as defined abovein Scheme 1.

Compounds of Formula I where Z is Z³ and R¹⁴ is —NR^(14a)R^(14b) can beprepared using the method described in Scheme 6 where R²⁵ and R²⁶ are asdefined above for R^(14a) and R^(14b), respectively.

Compounds of Formula I where Z is Z², R⁸ and R⁹ together form ═O, A isCH₂ or absent and B is N can be prepared as shown in Scheme 7:

wherein R³ and R²⁴-R²⁶ are as defined in Scheme 6.

Compounds of Formula I where Z is Z¹ and R⁵ is R¹⁶—C(O)— or R¹⁶—SO₂— canbe prepared as shown in Scheme 8:

where R³, R⁴, R⁷, R¹⁶ and R²⁴ are as defined above.

Compounds of Formula I where Z is Z¹ and R⁵ is hydroxyalkyl optionallysubstituted with an optionally substituted aryl or optionallysubstituted benzyl can be prepared as shown in Scheme 9:

where R³, R⁴, R⁷ and R²⁴ are as defined above and R²⁷ is selected fromthe group consisting of hydrogen, alkyl, optionally substituted aryl,and optionally substituted benzyl. The carbons to which R⁷ and R²⁷ areattached can be chiral centers and, thus, the configuration at thosecarbon atoms can be (R) or (S).

Another method for preparing compounds of Formula I where Z is Z¹ and R⁵is hydroxyalkyl optionally substituted with an optionally substitutedaryl or optionally substituted benzyl can be prepared as shown in Scheme10:

where R³, R⁴, R⁷, and R²⁴ are as defined above and R²⁸ and R²⁹ are eachindependently selected from the group consisting of hydrogen, alkyl,optionally substituted aryl, and optionally substituted benzyl. Thecarbon atoms to which R⁷, R²⁸ and R²⁹ are attached can be chiral centersand, thus, the configuration at those carbon atoms can be (R) or (S).

Compounds of Formula I where Z is Z² and R⁸ and R⁹ together form ═O canbe prepared as shown in Scheme 11:

where R¹-R³ and R¹⁰-R¹³ are as defined above for Formula I.

Accordingly, the amine and carboxylic acid are added in dry THF undernitrogen atmosphere. HOBT, EDCI, and triethylamine are added to themixture, and the mixture is stirred at room temperature overnight. Theresulting mixture is partitioned between ethyl acetate and 1.0 M sodiumchloride. The organic layer is separated, dried and concentrated to givea crude product, which can be purified by crystallization byhexane/ether.

Compounds of Formula I where Z is Z² and R⁸ and R⁹ both are hydrogen canbe prepared as shown in Scheme 12:

where R¹-R³ and R¹⁰-R¹³ are as described above.

Compounds of Formula I where Z is Z³ and R⁸ and R⁹ are both hydrogen canbe synthesized as shown in Scheme 13:

where R¹-R³ are as defined for Formula I, X is Cl or Br, and R′ can be,for example, alkenyl, optionally substituted phenyl, optionallysubstituted naphthyl, quinolinyl, pyridyl, or—(CH₂)_(p)-D-NR^(14a)R^(14b), wherein p, D, R^(14a) and R^(14b) are asdefined above.

For example, the amine, i.e., the piperidinyl compound, is dissolved inDMF and triethylamine added, followed by a halide R′CH₂X, wherein R′ isan optionally substituted phenyl. The reaction mixture is stirred for 12hours at 80° C. and the solvent is evaporated. The residue can bepurified by flash chromatography to give the desired product. When theappropriate benzyl halides are not available, corresponding aldehydes,R′C(O)H, can be used as follows: sodium triacetoxyborohydride (1.4 eq.)is added to a solution of an amine and an aldehyde in dichloroethane.The reaction mixture is stirred at room temperature for 12 hours. Afterthis period, the solution is decanted and purified by flashchromatography to give the desired product.

Compounds of Formula I where Z is Z³ and R⁸ and R⁹ together form ═O canbe synthesized using a method similar to that described in Scheme 11.

Compounds of Formula I where Z is Z⁴ can be prepared a shown in Scheme14:

where R¹-R³ are as defined for Formula I. For example, 0.5 mmol ofsulfonamide and approximately 0.5 mmol of the appropriate sulfonylchloride are dissolved in 5 mL of DCM and combined with 1.5 eq. DIEA(0.134 mL) that is added by syringe. The mixture is stirred overnight atroom temperature, and then concentrated under vacuum. The resultingproduct can be purified by using a column of silica gel with a gradientof 0% to 20% EtOAc in hexanes and the pure material is concentrated fromthe eluant.

Compounds of Formula I where Z is Z⁵ can be prepared as shown in Scheme15:

where R′ and R″ are as defined above for R³⁰ and R³¹.

Compounds of Formulae I-XIII where q is 0, 1 or 3 can be prepared usingmethods analogous to those described above for corresponding compoundswhere q is 2.

Testing of Compounds

Compounds of the present invention were assessed by calcium mobilizationand/or electrophysiological assays for calcium channel blocker activity.One aspect of the present invention is based on the use of the compoundsherein described as N-type calcium channel blockers. In one aspect ofthe present invention, it has been found that certain compounds hereindescribed show selectivity as N-type calcium channel blockers. Basedupon this property, these compounds are considered useful in treating,preventing, or ameliorating stroke, neuronal damage resulting from headtrauma, epilepsy, migraine, a mood disorder, schizophrenia, aneurodegenerative disorder (such as, e.g., Alzheimer's disease, ALS, orParkinson's disease), a psychosis, depression, anxiety, hypertension, orcardiac arrhythmia. The compounds of the present invention are alsoexpected to be effective in treating, preventing or ameliorating pain,such as acute pain, chronic pain, which includes but is not limited toneuropathic pain and inflammatory pain, or surgical pain.

More specifically, the present invention is directed to compounds ofFormulae I-XIII that are blockers of calcium channels. According to thepresent invention, those compounds having preferred N-type calciumchannel blocking properties exhibit an IC₅₀ of about 100 μM or less inthe calcium mobilization and/or electrophysiological assays describedherein. Preferably, the compounds of the present invention exhibit anIC₅₀ of 10 μM or less. Most preferably, the compounds of the presentinvention exhibit an IC₅₀ of about 1.0 μM or less. Compounds of thepresent invention can be tested for their N-type and L-type Ca²⁺ channelblocking activity by the following calcium mobilization and/orelectrophysiological assays.

In one embodiment, compounds useful in the present invention are thoserepresented by any one of Formulae I-XIII that exhibit selectivity forN-type calcium channels over L-type calcium channels in the calciummobilization and/or electrophysiological assays described herein. Thephrase “selectivity for N-type calcium channels over L-type calciumchannels” is used herein to mean that the ratio of an IC₅₀ for L-typechannel blocking activity for a compound of the present invention overan IC₅₀ for N-type channel blocking activity for the same compound ismore than 1, i.e., LTCC IC₅₀/NTCC IC₅₀>1. Preferably, compounds of thepresent invention exhibit an LTCC IC₅₀/NTCC IC₅₀ ratio of about 2 ormore, about 10 or more, about 20 or more, about 30 or more, about 50 ormore, or about 100 or more.

Calcium Mobilization and Electrophysiological Assay Protocols

Cell maintenance and differentiation. Unless noted otherwise, cellculture reagents were purchased from Mediatech of Hemdon, Md. IMR32cells (American Type Culture Collection, ATCC, Manassas, Va.) wereroutinely cultured in growth medium consisting of minimum essentialmedium containing 10% fetal bovine serum (FBS, Hyclone, Logan, Utah),100 U/mL penicillin, 100 μg/mL streptomycin, 2 mM L-glutamine, 1 mMsodium pyruvate, and 1×MEM non-essential amino acids. 80-90% confluentflasks of cells were differentiated using the following differentiationmedium: Growth medium plus 1 mM dibutyryl cyclic AMP (Sigma, St. Louis,Mo.), and 2.5 μM bromodeoxyuridine (Sigma). Cells were differentiatedfor 8 days by replacing differentiation medium every 2-3 days.

A7r5 (ATCC) cells were maintained and routinely cultured in A7r5 growthmedium consisting of Dulbecco's Modified Eagles Medium containing 10%FBS, 100 U/mL penicillin, 100 μg/mL streptomycin, 4 mM L-glutamine, and0.15% sodium bicarbonate. 80-90% confluent flasks of cells weredifferentiated using the following differentiation medium: A7r5 GrowthMedium plus 1 mM dibutyryl cyclic AMP (Sigma). Cells were differentiatedfor 8 days by replacing differentiation medium every 2-3 days.

Recombinant human embryonal kidney cells (HEK293, ATCC) stablytransfected with either N-type calcium channel (NTCC) subunits (α1b,α2δ, and β3) or L-type calcium channel (LTCC) subunits (α1c, α2δ, andβ1) were routinely cultured in growth medium consisting of Dulbecco'sModified Eagles Medium containing 10% FBS, 100 U/mL penicillin, 100μg/mL streptomycin, 4 mM L-glutamine, 500 μg/mL geneticin (G418), 20μg/mL Blasticidin S (InVivogen, San Diego, Calif.) and 500 μg/mL zeocin(InVivogen).

FLIPR Calcium Mobilization Assay for N-type Calcium Channel. One dayprior to performing this assay, differentiated IMR32 cells were treatedwith 1× CellStripper, and seeded on poly-D-lysine-coated 96-wellclear-bottom black plates (Becton Dickinson, Franklin Lakes, N.J.) at200,000 cells/well. On the day of the assay, the cell plates were washedwith IMR32 buffer (127 mM NaCl, 1 mM KCl, 2 mM MgCl₂, 700 μM NaH₂PO₄, 5mM CaCl₂, 5 mM NaHCO₃, 8 mM HEPES, 10 mM glucose, pH 7.4), thenpre-stimulated with KCl and loaded as follows: 0.05 mL of IMR32 buffer,0.05 mL of each compound tested diluted in IMR32 buffer containing 20 μMnitrendipine (Sigma), and 0.1 mL KCl dissolved in IMR32 buffer, plusFluo-4 were added (3 μM final concentration, Molecular Probes, Eugene,Oreg.). Final test compound concentrations ranged from about 846 μM toabout 17 μM, final nitrendipine concentration was 5 μM, and final KClconcentration was 90 mM. After 1 hour, the cells were washed twice with0.05 mL of each compound tested in nitrendipine-containing IMR32 buffer(no KCl or Fluo-4), and then replaced with 0.1 mL of each compoundtested in nitrendipine-containing IMR32 buffer. Plates were thentransferred to a Fluorimetric Imaging Plate Reader (FLIPR⁹⁶, MolecularDevices, Inc., Sunnyvale, Calif.) for assay. The FLIPR measured basalFluo-4 fluorescence for 315 seconds (i.e., 5 minutes and 15 seconds),then added 0.1 mL KCl agonist dissolved in IMR32 buffer and measuredfluorescence for another 45 seconds. Final test compound concentrationson the cells after FLIPR read ranged from about 846 μM to about 17 μM,final nitrendipine concentration was 5 μM, and final KCl concentrationwas 90 mM. Data were collected over the entire time course and analyzedusing Excel, Graph Pad Prism (version 3.02, Graph Pad, San Diego,Calif.), or an in-house non-linear regression analysis software.

FLIPR Calcium Mobilization Assay for L-type Calcium Channel. One dayprior to performing this assay, HEK293 cells stably expressingrecombinant rat L-type calcium channel (LTCC) subunits (α1c, α2δ, andβ1) were trypsinized, then seeded on poly-D-lysine-coated 96-wellclear-bottom black plates (Becton Dickinson, Franklin Lakes, N.J.) at75,000 cells/well. On the day of the assay, the plates were washed withLTCC wash buffer (127 mM NaCl, 2 mM MgCl₂, 700 μM NaH₂PO₄, 5 mM CaCl₂, 5mM NaHCO₃, 8 mM HEPES, 10 mM glucose, pH 7.4), then loaded with 0.1 mLof LTCC wash buffer containing Fluo-4 (3 μM final concentration,Molecular Probes, Eugene, Oreg.). After 1 hour, the cells were washedwith 0.1 mL LTCC wash buffer and resuspended in 0.05 mL LTCC assaybuffer (same composition as LTCC wash buffer). Plates were thentransferred to a FLIPR⁹⁶ for assay. The FLIPR measured basal Fluo-4fluorescence for 15 seconds, then added 0.05 mL of each compound testeddiluted in LTCC assay buffer at final concentrations ranging from about846 pM to about 17 μM. Fluo-4 fluorescence was then measured for 5minutes. 0.1 mL KCl agonist dissolved in LTCC assay buffer was thenadded to the cells to produce a final concentration of 90 mM KCl, andfluorescence was measured for another 45 seconds. Data were collectedover the entire time course and analyzed using Excel, Graph Pad Prism,or an in-house regression analysis software.

Alternative FLIPR Calcium Mobilization Assay for L-type Calcium Channel.Alternatively, the following cell line and procedure may be used for theFLIPR calcium mobilization assay for L-type calcium channel. One dayprior to performing this assay, differentiated A7r5 cells aretrypsinized, then seeded on tissue culture treated 96-well clear-bottomblack plates (Becton Dickinson, Franklin Lakes, N.J.) at a dilution of1:1 from a confluent T150 cm² flask. On the day of the assay, the platesare washed with A7r5 wash buffer (127 mM NaCl, 2 mM MgCl₂, 700 μMNaH₂PO₄, 5 mM CaCl₂, 5 mM NaHCO₃, 8 mM HEPES, 10 mM glucose, pH 7.4),then loaded with 0.1 mL of A7r5 wash buffer containing Fluo-4 (3 μMfinal concentration, Molecular Probes, Eugene, Oreg.). After 1 hour, thecells are washed with 0.1 mL A7r5 wash buffer and resuspended in 0.05 mLA7r5 assay buffer that is composed of A7r5 wash buffer plus 50 μMvalinomycin (Sigma). Plates are then transferred to a FLIPR⁹⁶ for assay.The FLIPR measures basal Fluo-4 fluorescence for 15 seconds, then adds0.05 mL of each compound tested diluted in A7r5 assay buffer at finalconcentrations ranging from about 846 pM to about 17 μM. Fluo-4fluorescence is then measured for 5 minutes. 0.1 mL KCl agonistdissolved in A7r5 assay buffer is then added to the cells to produce afinal concentration of 90 mM KCl, and fluorescence was measured foranother 45 seconds. Data were collected over the entire time course andanalyzed using Excel, Graph Pad Prism, or an in-house regressionanalysis software.

Cloning of N- and L-type calcium channel subunit open reading framecDNAs. Five cDNAs encoding subunits of the rat N- or L-type calciumchannels were cloned by PCR amplification in order to reconstitutefunctional channels in a heterologous system. These were the alpha1b(α1b), beta1 (β1), beta3 (β3), alpha2delta (α2δ), and alpha1c (α1c)subunit cDNAs. The alpha1b subunit cDNA has been described by Dubel etal. in Proc. Natl. Acad. Sci. U.S.A 89: 5058-5062 (1992). The beta1subunit cDNA has been described by Pragnell et al. in FEBS Lett. 291:253-258 (1991). The beta3 subunit cDNA has been described by Castellanoet al. in J. Biol. Chem. 268: 12359-12366 (1993). The alpha2deltasubunit cDNA has been described by Kim et al in Proc. Natl. Acad. Sci.U.S.A. 89: 3251-3255 (1992). The alpha1c subunit cDNA has been describedby Koch et al in J. Biol. Chem. 265: 17786-17791 (1990).

The 7.0 kb cDNA containing the entire α1b open reading frame (ORF) wasPCR amplified as two overlapping cDNA fragments, i.e., a 2.7 kb 5′fragment and a 4.4 kb 3′ fragment. The 5′ fragment was amplified fromrat brain cDNA using primers 1 (SEQ ID NO:1, TABLE 1) and 2 (SEQ IDNO:2, TABLE 1), and the 3′ fragment was amplified from rat spinal cordcDNA using primers 3 (SEQ ID NO:3, TABLE 1) and 4 (SEQ ID NO:4, TABLE1). The two fragments were joined by ligation at a common restrictionsite to create the entire 7.0 kb cDNA. This ORF encodes the proteinisoform generated by alternative splicing termed “+A ΔSFMG ΔET”according to the nomenclature of Lin et al (Neuron 18: 153-166 (1997)).The entire cDNA was sequenced with redundant coverage on both strands.The cDNA was then inserted into the mammalian expression vectorpcDNA6.2DEST (Invitrogen, Carlsbad Calif.) by homologous recombinationusing the Gateway system (Invitrogen).

The 1.8 kb cDNA encoding the β1 subunit, the 1.45 cDNA encoding thebeta3 subunit, and the 3.3 kb cDNA encoding the alpha2delta subunit werecloned by PCR amplification from rat spinal cord cDNA (β1) or brain cDNA(β3, α26). Primers 5 (SEQ ID NO:5, TABLE 1) and 6 (SEQ ID NO:6, TABLE 1)were used for the P1 cDNA amplification; primers 7 (SEQ ID NO:7,TABLE 1) and 8 (SEQ ID NO:8, TABLE 1) were used for the β3 cDNAamplification; and primers 9 (SEQ ID NO:9, TABLE 1) and 10 (SEQ IDNO:10, TABLE 1) were used for the α2δ cDNA amplification. PCR productswere subcloned and fully sequenced on both strands. Clones matching thereference sequence (β1: NM_(—)017346; β3: NM_(—)012828; α2δ: M86621) andthe gene's GenBank rat genomic DNA sequences were recombined into themammalian expression vector pcDNA3.2DEST (β1, β3) or pcDNA3.1-Zeo (α2δ),which had been modified to a vector compatible with the Gatewayrecombination system using the Gateway vector adaptor kit (Invitrogen).Proper recombination was confirmed by sequencing of recombinogenicregions. For P3 expression vector, proper protein expression wasconfirmed by Western blot analysis of lysates of transfected HEK293cells using a rabbit polyclonal antiserum directed against the rat P3subunit (USA Biological).

The 6.5 kb cDNA encoding the L-type calcium channel α1c subunit wascloned by PCR amplification from rat heart cDNA using primers 11 (SEQ IDNO:11, TABLE 1) and 12 (SEQ ID NO: 12, TABLE 1). The PCR fragment wassubcloned and fully sequenced on both strands to confirm its identity. Aclone matching consensus reference sequence M59786 and rat genomic DNAsequences was recombined into the mammalian expression vectorpcDNA6.2DEST. Sequences around the recombinogenic region were sequencedto confirm accurate recombination into the expression vector.

TABLE 1 PRIMER SEQUENCE SEQ ID NO. CACC ATG GTC CGC TTC GGG GAC 1 CCGTTC AGT GGC CTC CTC C 2 C TAG CAC CAG TGA TCC TGG TCTG 3 AGT GCG TTG TGAGCG CAG TA 4 CAC CAT GGT CCA GAA GAG CGG 5 TCTCAGCGGATGTAGACGCCT 6 CACCAT GTA TGA CGA CTC CTA C 7 GGT GGT CAG TAG CTG TCC TTA GG 8 CAC CAT GGCTGC TGG CTG CCT 9 AGA GGG TCA CCA TAG ATA GTG TCT G 10CACCATGATTCGGGCCTTCGCT 11 AGCCTGCGGACTACAGGTTGCTGAC 12

N-type Recombinant Cell Line Development. N-type calcium channelexpressing HEK-293 cells were created in two stages. Stage 1 was createdas follows. The rat α1b, and β3 cDNA expression constructs (2.5 μg each)were co-transfected into human embryonic kidney (HEK-293) cells byLipofectamine Plus reagent (Invitrogen), as per manufacturer'sinstructions. 24 hours later, cells were split in limiting dilution intomultiple 96-well plates in selection media containing 20 μg/mLblasticidin and 500 μg/mL geneticin, and incubated for 3 weeks at 37°C., 5% CO₂, 95% humidity. Plates containing ≦1 clone per well werecultured until wells positive for single clones were confluent.Individual clones were then arrayed into columns of a destination96-well plate, and partly split into 6-well plates for culturemaintenance. Array plates were washed once with IMR32 buffer and cellsloaded for 1 hour with 0.1 mL of IMR32 buffer containing Fluo-4 (3 μMfinal concentration, Molecular Probes). Then they were washed twice with0.1 mL of IMR32 buffer, and replaced with 0.1 mL IMR32 buffer. Plateswere then transferred to a FLIPR⁹⁶ for assay. The FLIPR measured basalFluo-4 fluorescence for 315 seconds, then added 0.1 mL KCl agonistdissolved in IMR32 buffer and measured fluorescence for another 45seconds. Final KCl concentration was 90 mM. Data were collected over theentire time course and analyzed using Excel, Graph Pad Prism, orActivity Base (version 5.1, IDBS, Parsippany, N.J.) software. The clonewith the greatest signal-to-noise ratio, best stability of response withpassage number, and best adhesion to PDL precoated plates (BectonDickinson) was expanded, characterized and used for stage 2 cell linedevelopment.

Stage 2 of N-type cell line development was carried out as follows. Therat α2δ cDNA expression construct (5 μg each) was transfected into thestage 1 N-type clonal cell line by Lipofectamine Plus reagent(Invitrogen), as per manufacturer's instructions. 24 hours later, cellswere split in limiting dilution into multiple 96-well plates inselection media containing 20 μg/mL blasticidin, 500 μg/mL geneticin,and 250 μg/mL zeocin and incubated for 3 weeks at 37° C., 5% CO₂, 95%humidity. Plates containing ≦1 clone per well were cultured and handledaccording to the same steps and procedures described above for the stage1 cell line. The three clones with the greatest signal-to-noise, beststability of response with passage number, and best adhesion to PDLprecoated plates (Becton Dickinson) were expanded, characterized andtested in electrophysiology for the best current size, N-typepharmacology, N-type characteristic current-voltage relationship andkinetics as described below.

L-type Recombinant Cell Line Development. L-type calcium channelexpressing HEK-293 cells were created in two stages. Stage 1 was createdas follows. The rat α1c, and β1 cDNA expression constructs (2.5 μg each)were co-transfected into human embryonic kidney (HEK-293) cells byLipofectamine Plus reagent (Invitrogen), as per manufacturer'sinstructions. 24 hours later, cells were split in limiting dilution intomultiple 96-well plates in selection media containing 20 μg/mLblasticidin and 500 μg/mL geneticin, and incubated for 3 weeks at 37°C., 5% CO₂, 95% humidity. Plates containing ≦1 clone per well werecultured until wells positive for single clones were confluent.Individual clones were then arrayed into columns of a destination96-well plate, and partly split into 6-well plates for culturemaintenance. Array plates were washed once with LTCC wash (or assay)buffer and cells loaded for 1 hour with 0.1 mL of LTCC buffer containingFluo-4 (3 μM final concentration, Molecular Probes). Then they werewashed twice with 0.1 mL of LTCC buffer, and replaced with 0.1 mL LTCCbuffer. Plates were then transferred to a FLIPR⁹⁶ for assay. The FLIPRmeasured basal Fluo-4 fluorescence for 315 seconds, then added 0.1 mLKCl agonist dissolved in LTCC buffer and measured fluorescence foranother 45 seconds. Final KCl concentration was 90 mM. Data werecollected over the entire time course and analyzed using Excel, GraphPad Prism, or Activity Base software. The clone with the greatestsignal-to-noise ratio, best stability of response with passage number,and best adhesion to PDL precoated plates (Becton Dickinson) wasexpanded, characterized and used for stage 2 cell line development.

Stage 2 of L-type cell line development was carried out as follows. Therat α2δ cDNA expression construct (5 μg each) was transfected into thestage 1 L-type clonal cell line by Lipofectamine Plus reagent(Invitrogen), as per manufacturer's instructions. 24 hours later, cellswere split in limiting dilution into multiple 96-well plates inselection media containing 20 μg/mL blasticidin, 500 μg/mL geneticin,and 250 μg/mL zeocin and incubated for 3 weeks at 37° C., 5% CO₂, 95%humidity. Plates containing ≦1 clone per well were cultured and handledaccording to the same steps and procedures described above for the stage1 cell line. The three clones with the greatest signal-to-noise, beststability of response with passage number, and best adhesion to PDLprecoated plates (Becton Dickinson) were expanded and characterized.

N-type Electrophysiology in Recombinant Cells. For electrophysiologicalrecording, the cells expressing α1b, β3 and α2δ subunits were seeded on35-mm culture Petri dishes at a density of approximately 10⁴ cells/dishand kept in an incubator for up to three days for subsequent recordings.For recordings, the dishes were positioned on the stage of an invertedmicroscope (Nikon, Eclipse E600, Japan) and superfused with a bathsolution comprised of BaCl₂ (11 mM), MgCl₂ (1.5 mM), HEPES (10 mM), TEAchloride (120 mM), glucose (10 mM) adjusted to pH 7.4 with KOH.Whole-cell voltage-clamp recordings were made using conventionalpatch-clamp techniques (Hamill et al., Pfluegers Arch. 391: 85-100(1981)) at room temperature (22-24° C.). The patch-clamp pipettes werepulled from WPI, thick-walled borosilicate glass (WPI, Sarasota, Fla.).Currents were recorded using an Axopatch 200A amplifier (AxonInstruments, Union City, Calif.) and were leak-subtracted (P/4),low-pass filtered (1 kHz, 4-pole Bessel), digitized (20-50-μsintervals), and stored using Digidata 1200 B interface andPclamp8.0/Clampex software (Axon Instruments, Union City, Calif.). Thepipettes were back-filled with internal solution containing CsCl (110mM), MgCl₂ (3 mM), EGTA (3 mM), HEPES (40 mM), Mg-ATP (4 mM), Na₂GTP(0.5 mM), and adjusted to pH 7.2 with CsOH. The pipette resistanceranged from 2 to 3 MOhm and was compensated by 75-80% by the built-inelectronic circuitry.

Currents were elicited by stepping from a holding potential of −90 mV to0 mV for 20 ms every 20 sec. At the −90 mV membrane voltage about 50% ofchannels were in the inactivated state, and thus contact with a blockerwould involve interaction with both resting and inactivated channels.Every drug was applied at 3 to 4 concentrations increasing in acumulative manner. Fractional inhibition levels in steady-state wereused to draw the partial inhibition concentration curves to get the IC₅₀(i.e. concentration causing 50% reduction in the size of the response)values at −90 mV.

Stock solutions of each test compound were prepared using DMSO. Serialdilutions to desired concentrations were done with bath solution;concentration of DMSO in final solutions was 0.1%. Drugs were applied bygravity flow using a plane multi-barrel array shooter positioned 0.5 mmapart from the cell.

All curve fittings were carried out using Origin software (version 5.0,Microcal). A Hill equation was fit to the concentration-inhibitioncurves to determine IC₅₀ values.

N-type Electrophysiology in Neuronal Cells. To determine dissociationconstants in resting versus inactivated state for N-type calciumchannels, neuronal cells that endogenously express N-type calciumchannels can be used. For electrophysiological recording, the neuronalcells expressing N-type calcium channels are seeded on 35-mm culturePetri dishes at a density of approximately 10⁴ cells/dish and kept in anincubator for up to three days for subsequent recordings. Forrecordings, the dishes are positioned on the stage of an invertedmicroscope (Nikon, Eclipse E600, Japan) and superfused with a bathsolution comprised of BaCl₂ (11 mM), MgCl₂ (1.5 mM), HEPES (10 mM), TEAchloride (120 mM), glucose (10 mM) adjusted to pH 7.4 with KOH.Whole-cell voltage-clamp recordings are made using conventionalpatch-clamp techniques (Hamill et al., Pfluegers Arch. 391: 85-100(1981)) at room temperature (22-24° C.). The patch-clamp pipettes arepulled from WPI, thick-walled borosilicate glass (WPI, Sarasota, Fla.).Currents are recorded using an Axopatch 200A amplifier (AxonInstruments, Union City, Calif.) and leak-subtracted (P/4), low-passfiltered (1 kHz, 4-pole Bessel), digitized (20-50-μs intervals), andstored using Digidata 1200 B interface and Pclamp8.0/Clampex software(Axon Instruments, Union City, Calif.). The pipettes are back-filledwith internal solution containing CsCl (110 mM), MgCl₂ (3 mM), EGTA (3mM), HEPES (40 mM), Mg-ATP (4 mM), Na₂GTP (0.5 mM), and adjusted to pH7.2 with CsOH. The pipette resistance ranges from 2 to 3 MOhm and iscompensated by 75-80% by the built-in electronic circuitry.

Currents are elicited by stepping from a holding potential of −90 mV to0 mV for 20 ms every 10 sec. At the −90 mV membrane voltage a proportionof channels is in the inactivated state, and thus contact with a blockerwould involve interaction with both resting and inactivated channels.This protocol is used as a first tier screen. For dissection of twocomponents of inhibition (resting block with the apparent dissociationconstant K_(r) and inactivated state block with K_(i)), steady-stateinactivation curves are collected using a double-pulse protocol.Three-second long depolarizing pre-pulse incrementing in 10 mV steps isfollowed by a 10 ms test pulse to 0 mV.

Stock solutions of each test compound are prepared using DMSO. Serialdilutions to desired concentrations are done with bath solution;concentration of DMSO in final solutions is 0.1%. Drugs are applied bygravity flow using a plane multi-barrel array shooter positioned 1 mmapart from the cell.

All curve fittings can be carried out using Origin software (version5.0, Microcal). A Hill equation is used to fit theconcentration-response curves and to determine IC₅₀ values. A Boltzmanequation is used to fit inactivation curves, returning half-inactivationvoltage, V_(0.5), slope p and the amplitude of current at the mostnegative voltage where eventually all channels are in the resting state.These parameters are used to calculate the apparent dissociationconstants: K_(r)=((Ab/Ac)/(1−(Ab/Ac))[b]) where [b] is the drugconcentration, Ac is the maximum test current amplitude in controlconditions and Ab is the maximum test current amplitude in the presenceof a blocker; K_(i)=[b]/((exp(−(dx/p))*(1+([b]/K_(r)))−1) where dx isthe difference between half-inactivation voltage V_(0.5) in the presenceand absence of drug and p is the slope.

In Vivo Pharmacology

The compounds of the present invention can be tested for in vivoanticonvulsant activity after i.v., p.o., or i.p. injection using any ofa number of anticonvulsant tests in mice, including the maximumelectroshock seizure test (MES). Maximum electroshock seizures areinduced in male NSA mice weighing between 15-20 g and in maleSprague-Dawley rats weighing between 200-225 g by application of current(for mice: 50 mA, 60 pulses/sec, 0.8 msec pulse width, 1 sec duration,D.C.; for rats: 99 mA, 125 pulses/sec, 0.8 msec pulse width, 2 secduration, D.C.) using a Ugo Basile ECT device (Model 7801). Mice arerestrained by gripping the loose skin on their dorsal surface andsaline-coated corneal electrodes are held lightly against the twocomeae. Rats are allowed free movement on the bench top and ear-clipelectrodes are used. Current is applied and animals are observed for aperiod of up to 30 seconds for the occurrence of a tonic hindlimbextensor response. A tonic seizure is defined as a hindlimb extension inexcess of 90 degrees from the plane of the body. Results can be treatedin a quantal manner.

The compounds can be tested for their antinociceptive activity in theformalin model as described in Hunskaar, S., O. B. Fasmer, and K. Hole,J. Neurosci. Methods 14: 69-76 (1985). Male Swiss Webster NIH mice(20-30 g; Harlan, San Diego, Calif.) can be used in all experiments.Food is withdrawn on the day of experiment. Mice are placed inPlexiglass jars for at least 1 hour to acclimate to the environment.Following the acclimation period mice are weighed and given either thecompound of interest administered i.p. or p.o., or the appropriatevolume of vehicle (10% Tween-80) as control. Fifteen minutes after thei.p. dosing, and 30 minutes after the p.o. dosing mice are injected withformalin (20 μL of 5% formaldehyde solution in saline) into the dorsalsurface of the right hind paw. Mice are transferred to the Plexiglassjars and monitored for the amount of time spent licking or biting theinjected paw. Periods of licking and biting are recorded in 5-minuteintervals for 1 hour after the formalin injection. All experiments aredone in a blinded manner during the light cycle. The early phase of theformalin response is measured as licking/biting between 0-5 minutes, andthe late phase is measured from 15-50 minutes. Differences betweenvehicle and drug treated groups can be analyzed by one-way analysis ofvariance (ANOVA). A P value <0.05 is considered significant. Compoundsare considered to be efficacious for treating acute and chronic pain ifthey have activity in blocking both the early and second phase offormalin-induced paw-licking activity.

Compounds can be tested for their potential to treat chronic pain (i.e.,antiallodynic and antihyperalgesic activities) using the Chung model ofperipheral neuropathy (Kim and Chung, Pain 50: 355-363 (1992)). MaleSprague-Dawley rats weighing between 200-225 g are anesthetized withhalothane (1-3% in a mixture of 70% air and 30% oxygen), and their bodytemperature controlled during anesthesia through use of a homeothermicblanket. A 2-cm dorsal midline incision is then made at the L5 and L6level, and the para-vertebral muscle groups retracted bilaterally. L5and L6 spinal nerves are then exposed, isolated, and tightly ligatedwith 6-0 or 7-0 silk suture. A sham operation is performed exposing thecontralateral L5 and L6 spinal nerves, without ligating, as a negativecontrol.

Tactile Allodynia Sensitivity to non-noxious mechanical stimuli can bemeasured in animals to assess tactile allodynia. Rats are transferred toan elevated testing cage with a wire mesh floor and allowed to acclimatefor five to ten minutes. A series of von Frey monofilaments are appliedto the plantar surface of the hindpaw to determine the animal'swithdrawal threshold. The first filament used possesses a bucklingweight of 9.1 gms (0.96 log value) and is applied up to five times tosee if it elicits a withdrawal response. If the animal has a withdrawalresponse, then the next lightest filament in the series would be appliedup to five times to determine if it also could elicit a response. Thisprocedure is repeated with subsequent lesser filaments until there is noresponse and the identity of the lightest filament that elicits aresponse is recorded. If the animal does not have a withdrawal responsefrom the initial 9.1 gms filament, then subsequent filaments ofincreased weight are applied until a filament elicits a response and theidentity of this filament is recorded. For each animal, threemeasurements are made at every time point to produce an averagewithdrawal threshold determination. Tests can be performed prior to, andat 1, 2, 4 and 24 hours post drug administration.

Mechanical Hyperalgesia Sensitivity to noxious mechanical stimuli can bemeasured in animals using the paw pressure test to assess mechanicalhyperalgesia. In rats, hind paw withdrawal thresholds (“PWT”), measuredin grams, in response to a noxious mechanical stimulus are determinedusing an analgesymeter (Model 7200, commercially available from UgoBasile of Italy), as described in Stein (Biochemistry & Behavior 31:451-455 (1988)). The rat's paw is placed on a small platform, and weightis applied in a graded manner up to a maximum of 250 grams. The endpointis taken as the weight at which the paw is completely withdrawn. PWT isdetermined once for each rat at each time point. PWT can be measuredonly in the injured paw, or in both the injured and non-injured paw. Inone non-limiting embodiment, mechanical hyperalgesia associated withnerve injury induced pain (neuropathic pain) can be assessed in rats.Rats are tested prior to surgery to determine a baseline, or normal,PWT. Rats are tested again 2 to 3 weeks post-surgery, prior to, and atdifferent times after (e.g. 1, 3, 5 and 24 hr) drug administration. Anincrease in PWT following drug administration indicates that the testcompound reduces mechanical hyperalgesia.

Pharmaceutical Compositions

Although a compound of the present invention may be administered to amammal in the form of a raw chemical without any other componentspresent, the compound is preferably administered as part of apharmaceutical composition containing the compound combined with asuitable pharmaceutically acceptable carrier. Such a carrier can beselected from pharmaceutically acceptable excipients and auxiliaries.

Pharmaceutical compositions within the scope of the present inventioninclude all compositions where a compound of the present invention iscombined with a pharmaceutically acceptable carrier. In a preferredembodiment, the compound is present in the composition in an amount thatis effective to achieve its intended therapeutic purpose. Whileindividual needs may vary, a determination of optimal ranges ofeffective amounts of each compound is within the skill of the art.Typically, the compounds may be administered to a mammal, e.g., a human,orally at a dose of from about 0.0025 to about 1500 mg per kg bodyweight of the mammal, or an equivalent amount of a pharmaceuticallyacceptable salt, prodrug, or solvate thereof, per day to treat, preventor ameliorate the particular disorder. A useful oral dose of a compoundof the present invention administered to a mammal is from about 0.0025to about 50 mg per kg body weight of the mammal, or an equivalent amountof the pharmaceutically acceptable salt, prodrug, or solvate thereof.For intramuscular injection, the dose is typically about one-half of theoral dose.

A unit oral dose may comprise from about 0.01 to about 50 mg, andpreferably about 0.1 to about 10 mg, of the compound. The unit dose canbe administered one or more times daily, e.g., as one or more tablets orcapsules, each containing from about 0.01 to about 50 mg of thecompound, or an equivalent amount of a pharmaceutically acceptable saltor solvate thereof.

A pharmaceutical composition of the present invention can beadministered to any animal that may experience the beneficial effects ofa compound of the present invention. Foremost among such animals aremammals, e.g., humans and companion animals, although the invention isnot intended to be so limited.

A pharmaceutical composition of the present invention can beadministered by any means that achieves its intended purpose. Forexample, administration can be by the oral, parenteral, subcutaneous,intravenous, intramuscular, intraperitoneal, transdermal, intranasal,transmucosal, rectal, intravaginal or buccal route, or by inhalation.The dosage administered and route of administration will vary, dependingupon the circumstances of the particular subject, and taking intoaccount such factors as age, health, and weight of the recipient,condition or disorder to be treated, kind of concurrent treatment, ifany, frequency of treatment, and the nature of the effect desired.

In one embodiment, a pharmaceutical composition of the present inventioncan be administered orally and is formulated into tablets, dragees,capsules or an oral liquid preparation. In one embodiment, the oralformulation comprises extruded multiparticulates comprising the compoundof the invention.

Alternatively, a pharmaceutical composition of the present invention canbe administered rectally, and is formulated in suppositories.

Alternatively, a pharmaceutical composition of the present invention canbe administered by injection.

Alternatively, a pharmaceutical composition of the present invention canbe administered transdermally.

Alternatively, a pharmaceutical composition of the present invention canbe administered by inhalation or by intranasal or transmucosaladministration.

Alternatively, a pharmaceutical composition of the present invention canbe administered by the intravaginal route.

A pharmaceutical composition of the present invention can contain fromabout 0.01 to 99 percent by weight, and preferably from about 0.25 to 75percent by weight, of active compound(s).

A method of the present invention, such as a method for treating,preventing, or ameliorating a disorder responsive to the blockade ofcalcium channels in an animal in need thereof, can further compriseadministering a second therapeutic agent to the animal in combinationwith a compound of the present invention. In one embodiment, the othertherapeutic agent is administered in an effective amount.

Effective amounts of the other therapeutic agents are known to thoseskilled in the art. However, it is well within the skilled artisan'spurview to determine the other therapeutic agent's optimaleffective-amount range.

A compound of the present invention (i.e., the first therapeutic agent)and the second therapeutic agent can act additively or, in oneembodiment, synergistically. In one embodiment, a compound of thepresent invention is administered concurrently with a second therapeuticagent; for example, a single composition comprising both an effectiveamount of a compound of any of Formulae I-XIII, and an effective amountof the second therapeutic agent can be administered. Accordingly, thepresent invention further provides a pharmaceutical compositioncomprising a combination of a compound of the present invention, thesecond therapeutic agent, and a pharmaceutically acceptable carrier.Alternatively, a first pharmaceutical composition comprising aneffective amount of a compound of any of Formulae I-XIII and a secondpharmaceutical composition comprising an effective amount of the secondtherapeutic agent can be concurrently administered. In anotherembodiment, an effective amount of a compound of the present inventionis administered prior or subsequent to administration of an effectiveamount of the second therapeutic agent. In this embodiment, the compoundof the present invention is administered while the second therapeuticagent exerts its therapeutic effect, or the second therapeutic agent isadministered while the compound of the present invention exerts itstherapeutic effect for treating, preventing or ameliorating a disorderor condition.

The second therapeutic agent can be an opioid agonist, a non-opioidanalgesic, a non-steroidal anti-inflammatory agent, an antimigraineagent, a Cox-II inhibitor, a β-adrenergic blocker, an anticonvulsant, anantidepressant, an anticancer agent, an agent for treating addictivedisorder, an agent for treating Parkinson's disease and parkinsonism, anagent for treating anxiety, an agent for treating epilepsy, an agent fortreating a seizure, an agent for treating a stroke, an agent fortreating a pruritic condition, an agent for treating psychosis, an agentfor treating ALS, an agent for treating a cognitive disorder, an agentfor treating a migraine, an agent for treating vomiting, an agent fortreating dyskinesia, or an agent for treating depression, or a mixturethereof.

Examples of useful opioid agonists include, but are not limited to,alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, proheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tilidine,tramadol, pharmaceutically acceptable salts thereof, and mixturesthereof.

In certain embodiments, the opioid agonist is selected from codeine,hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine,morphine, tramadol, oxymorphone, pharmaceutically acceptable saltsthereof, and mixtures thereof.

Examples of useful non-opioid analgesics include non-steroidalanti-inflammatory agents, such as aspirin, ibuprofen, diclofenac,naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, andpharmaceutically acceptable salts thereof, and mixtures thereof.Examples of other suitable non-opioid analgesics include the following,non limiting, chemical classes of analgesic, antipyretic, nonsteroidalantiinflammatory drugs: salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin; paraaminophennol derivatives including acetaminophen and phenacetin; indoleand indene acetic acids, including indomethacin, sulindac, and etodolac;heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac;anthranilic acids (fenamates), including mefenamic acid, andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);and alkanones, including nabumetone. For a more detailed description ofthe NSAIDs, see Paul A. Insel, Analgesic Antipyretic andAntiinflammatory Agents and Drugs Employed in the Treatment of Gout, inGoodman & Gilman's The Pharmacological Basis of Therapeutics 617-57(Perry B. Molinhoff and Raymond W. Ruddon eds., 9th ed 1996) and Glen R.Hanson, Analgesic, Antipyretic and Anti Inflammatory Drugs in Remington:The Science and Practice of Pharmacy Vol II 1196-1221 (A. R. Gennaro ed.19th ed. 1995) which are hereby incorporated by reference in theirentireties. Suitable Cox-II inhibitors and 5-lipoxygenase inhibitors, aswell as combinations thereof, are described in U.S. Pat. No. 6,136,839,which is hereby incorporated by reference in its entirety. Examples ofuseful Cox TI inhibitors include, but are not limited to, rofecoxib andcelecoxib.

Examples of useful antimigraine agents include, but are not limited to,alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocomine,ergocominine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxoneacetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine,methysergide, metoprolol, naratriptan, oxetorone, pizotyline,propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone,zolmitriptan, and mixtures thereof.

Examples of useful β-adrenergic blockers include, but are not limitedto, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol,betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol,bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol,carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol,dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol,mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol,nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol,practolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol,tertatolol, tilisolol, timolol, toliprolol, and xibenolol.

Examples of useful anticonvulsants include, but are not limited to,acetylpheneturide, albutoin, aloxidone, aminoglutethimide,4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate,calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam,decimemide, diethadione, dimethadione, doxenitroin, eterobarb,ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin,5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate,mephenyloin, mephobarbital, metharbital, methetoin, methsuximide,5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin,narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione,phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide,phenylmethylbarbituric acid, phenyloin, phethenylate sodium, potassiumbromide, pregabaline, primidone, progabide, sodium bromide, solanum,strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine,topiramate, trimethadione, valproic acid, valpromide, vigabatrin, andzonisamide.

Examples of useful antidepressants include, but are not limited to,binedaline, caroxazone, citalopram, (S)-citalopram, dimethazan,fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine,oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone,benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin,phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole,mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide,amoxapine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine,imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine,nortriptyline, noxiptilin, opipramol, pizotyline, propizepine,protriptyline, quinupramine, tianeptine, trimipramine, adrafinil,benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone,febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine,hematoporphyrin, hypericin, levophacetoperane, medifoxamine,milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline,prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride,sulpiride, tandospirone, thozalinone, tofenacin, toloxatone,tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimeldine.

Examples of useful anticancer agents include, but are not limited to,acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin,aldesleukin, altretamine, ambomycin, ametantrone acetate,aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase,asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa,bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin,bleomycin sulfate, brequinar sodium, bropirimine, busulfan,cactinomycin, calusterone, caracemide, carbetimer, carboplatin,carmustine, carubicin hydrochloride, carzelesin, cedefingol,chlorambucil, cirolemycin, and cisplatin.

Therapeutic agents useful for treating or preventing an addictivedisorder include, but are not limited to, methadone, desipramine,amantadine, fluoxetine, buprenorphine, an opiate agonist,3-phenoxypyridine, or a serotonin antagonist.

Examples of useful therapeutic agents for treating or preventingParkinson's disease and parkinsonism include, but are not limited to,carbidopa/levodopa, pergolide, bromocriptine, ropinirole, pramipexole,entacapone, tolcapone, selegiline, amantadine, and trihexyphenidylhydrochloride.

Examples of useful therapeutic agents for treating or preventing anxietyinclude, but are not limited to, benzodiazepines, such as alprazolam,brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate,demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam,lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam,quazepam, temazepam, and triazolam; non-benzodiazepine agents, such asbuspirone, gepirone, ipsapirone, tiospirone, zolpicone, zolpidem, andzaleplon; tranquilizers, such as barbituates, e.g., amobarbital,aprobarbital, butabarbital, butalbital, mephobarbital, methohexital,pentobarbital, phenobarbital, secobarbital, and thiopental; andpropanediol carbamates, such as meprobamate and tybamate.

Examples of useful therapeutic agents for treating or preventingepilepsy or seizure include, but are not limited to, carbamazepine,ethosuximide, gabapentin, lamotrigine, phenobarbital, phenyloin,primidone, valproic acid, trimethadione, benzodiazepines, gamma-vinylGABA, acetazolamide, and felbamate.

Examples of useful therapeutic agents for treating or preventing strokeinclude, but are not limited to, anticoagulants such as heparin, agentsthat break up clots such as streptokinase or tissue plasminogenactivator, agents that reduce swelling such as mannitol orcorticosteroids, and acetylsalicylic acid.

Examples of useful therapeutic agents for treating or preventing apruritic condition include, but are not limited to, naltrexone;nalmefene; danazol; tricyclics such as amitriptyline, imipramine, anddoxepin; antidepressants such as those given below; menthol; camphor;phenol; pramoxine; capsaicin; tar; steroids; and antihistamines.

Examples of useful therapeutic agents for treating or preventingpsychosis include, but are not limited to, phenothiazines such aschlorpromazine hydrochloride, mesoridazine besylate, and thoridazinehydrochloride; thioxanthenes such as chloroprothixene and thiothixenehydrochloride; clozapine; risperidone; olanzapine; quetiapine;quetiapine fumarate; haloperidol; haloperidol decanoate; loxapinesuccinate; molindone hydrochloride; pimozide; and ziprasidone.

Examples of useful therapeutic agents for treating or preventing ALSinclude, but are not limited to, baclofen, neurotrophic factors,riluzole, tizanidine, benzodiazepines such as clonazepan and dantrolene.

Examples of useful therapeutic agents for treating or preventingcognitive disorders include, but are not limited to, agents for treatingor preventing dementia such as tacrine; donepezil; ibuprofen;antipsychotic drugs such as thioridazine and haloperidol; andantidepressant drugs such as those given below.

Examples of useful therapeutic agents for treating or preventing amigraine include, but are not limited to, sumatriptan; methysergide;ergotamine; caffeine; and beta-blockers such as propranolol, verapamil,and divalproex.

Examples of useful therapeutic agents for treating or preventingvomiting include, but are not limited to, 5-HT3 receptor antagonistssuch as ondansetron, dolasetron, granisetron, and tropisetron; dopaminereceptor antagonists such as prochlorperazine, thiethylperazine,chlorpromazine, metoclopramide, and domperidone; glucocorticoids such asdexamethasone; and benzodiazepines such as lorazepam and alprazolam.

Examples of useful therapeutic agents for treating or preventingdyskinesia include, but are not limited to, reserpine and tetrabenazine.

Examples of useful therapeutic agents for treating or preventingdepression include, but are not limited to, tricyclic antidepressantssuch as amitryptyline, amoxapine, bupropion, clomipramine, desipramine,doxepin, imipramine, maprotiline, nefazadone, nortriptyline,protriptyline, trazodone, trimipramine, and venlafaxine; selectiveserotonin reuptake inhibitors such as citalopram, (S)-citalopram,fluoxetine, fluvoxamine, paroxetine, and setraline; monoamine oxidaseinhibitors such as isocarboxazid, pargyline, phenelzine, andtranylcypromine; and psychostimulants such as dextroamphetamine andmethylphenidate.

A pharmaceutical composition of the present invention is preferablymanufactured in a manner which itself will be known in view of theinstant disclosure, for example, by means of conventional mixing,granulating, dragee-making, dissolving, extrusion, or lyophilizingprocesses. Thus, pharmaceutical compositions for oral use can beobtained by combining the active compound with solid excipients,optionally grinding the resulting mixture and processing the mixture ofgranules, after adding suitable auxiliaries, if desired or necessary, toobtain tablets or dragee cores.

Suitable excipients include fillers such as saccharides (for example,lactose, sucrose, mannitol or sorbitol), cellulose preparations, calciumphosphates (for example, tricalcium phosphate or calcium hydrogenphosphate), as well as binders such as starch paste (using, for example,maize starch, wheat starch, rice starch, or potato starch), gelatin,tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodiumcarboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, one ormore disintegrating agents can be added, such as the above-mentionedstarches and also carboxymethyl-starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodiumalginate.

Auxiliaries are typically flow-regulating agents and lubricants such as,for example, silica, talc, stearic acid or salts thereof (e.g.,magnesium stearate or calcium stearate), and polyethylene glycol. Drageecores are provided with suitable coatings that are resistant to gastricjuices. For this purpose, concentrated saccharide solutions may be used,which may optionally contain gum arabic, talc, polyvinyl pyrrolidone,polyethylene glycol and/or titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures. In order to producecoatings resistant to gastric juices, solutions of suitable cellulosepreparations such as acetylcellulose phthalate orhydroxypropymethyl-cellulose phthalate can be used. Dye stuffs orpigments may be added to the tablets or dragee coatings, for example,for identification or in order to characterize combinations of activecompound doses.

Examples of other pharmaceutical preparations that can be used orallyinclude push-fit capsules made of gelatin, or soft, sealed capsules madeof gelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules can contain a compound in the form of granules, which may bemixed with fillers such as lactose, binders such as starches, and/orlubricants such as talc or magnesium stearate and, optionally,stabilizers, or in the form of extruded multiparticulates. In softcapsules, the active compounds are preferably dissolved or suspended insuitable liquids, such as fatty oils or liquid paraffin. In addition,stabilizers may be added.

Possible pharmaceutical preparations for rectal administration include,for example, suppositories, which consist of a combination of one ormore active compounds with a suppository base. Suitable suppositorybases include natural and synthetic triglycerides, and paraffinhydrocarbons, among others. It is also possible to use gelatin rectalcapsules consisting of a combination of active compound with a basematerial such as, for example, a liquid triglyceride, polyethyleneglycol, or paraffin hydrocarbon.

Suitable formulations for parenteral administration include aqueoussolutions of the active compound in a water-soluble form such as, forexample, a water-soluble salt, alkaline solution, or acidic solution.Alternatively, a suspension of the active compound may be prepared as anoily suspension. Suitable lipophilic solvents or vehicles for such assuspension may include fatty oils (for example, sesame oil), syntheticfatty acid esters (for example, ethyl oleate), triglycerides, or apolyethylene glycol such as polyethylene glycol-400 (PEG-400). Anaqueous suspension may contain one or more substances to increase theviscosity of the suspension, including, for example, sodiumcarboxymethyl cellulose, sorbitol, and/or dextran. The suspension mayoptionally contain stabilizers.

The following examples are illustrative, but not limiting, of thecompounds, compositions and methods of the present invention. Suitablemodifications and adaptations of the variety of conditions andparameters normally encountered in clinical therapy and which areobvious to those skilled in the art in view of this disclosure arewithin the spirit and scope of the invention.

EXAMPLES Example 1N-Cyclopropyl-N-piperidin-3-yl-3-trifluoromethylbenzenesulfonamidehydrochloride (6)

N-Cyclopropyl-N-piperidin-3-yl-3-trifluoromethylbenzenesulfonamidehydrochloride (6) was prepared as follows. NaB(O₂CCH₃)₃H (14 g, 66 mmol,Aldrich) was added to a mixture of N-tert-butoxycarbonylpiperidine-3-one(1) (10 g, 50 mmol, Aldrich), aminocyclopropyl (2) (3 g, 52.5 mmol,Aldrich), molecular sieves (4 Å beads, 20 g, Aldrich) in dichloroethane(DCE, 200 mL) at 0° C. The resulting mixture was stirred at roomtemperature for 24 hours. The reaction mixture was quenched with MeOH (2mL), filtered over Celite, washed with water, 2N NaOH and concentratedunder vacuum to afford crude 3-(cyclopropylamino)piperidine-1-carboxylicacid tert-butyl ester (3) as a colorless oil.

3-Trifluoromethylphenylsulfonyl chloride (4) (12 g, 49 mmol, Aldrich)was added to a mixture of the crude compound 3, triethylamine (TEA, 10mL) and dichloromethane (DCM, 10 mL) at room temperature. The resultingmixture was heated and stirred at 37° C. for 2 days. The reactionmixture was cooled to room temperature, washed with water (10 mL) andthen with brine, and concentrated and purified by column (silica gel)eluting with EtOAc/hexanes (3/7) to afford3-[N-cyclopropyl-N-(3-trifluoromethylbenzenesulfonyl)amino]piperidine-1-carboxylicacid tert-butyl ester (5) as a sticky oil (10 g, yield 45% in twosteps), which was dissolved in 100 mL of 1,4-dioxane. HCl (10 mL,concentrated aq.) was added to the 1,4-dioxane solution at roomtemperature. The resulting mixture was stirred at room temperature for48 hours, and concentrated under vacuum. The residue was washed withethyl ether, and dried to obtain the desired title compound 6 as an oil(6.5 g, 81%). ¹H NMR (400 MHz, CD₃OD): δ 8.22 (d, j=7.9 Hz, 1H), 8.17(s, 1H), 8.06 (d, j=7.8 Hz, 1H), 7.90 (d, 1H, j=7.8 Hz, 1H), 4.17-4.24(m, 1H), 3.34-3.38 (m, 2H), 3.22-3.29 (m, 1H), 2.87-2.95 (m, 1H),1.98-2.18 (m, 3H), 1.68-1.82 (m, 2H), 1.04-1.09 (m, 1H), 0.79-0.92 (m,3H); LC: 100%; MS: m/z=349 (M+1).

Example 2(2S)N-[1-(2-Amino-4-methylpentanoyl)piperidin-3-yl]-N-cyclopropyl-3-trifluoromethylbenzenesulfonamide(8)

(2S)N-[1-(2-Amino-4-methylpentanoyl)-piperidin-3-yl]-N-cyclo-propyl-3-trifluoromethylbenzenesulfonamide(8) was prepared as follows. A solution of compound 6 (see Example 1)(300 mg, 0.78 mmol), triethylamine (TEA, 0.5 mL), 1-hydroxybenzotriazole(HOBT) (100 mg), compound 2 (0.2 g, 0.86 mmol, Adv. Chem. Tech.), anddichloromethane (DCM, 4 mL) was cooled with ice-water and treated withdiisopropyl azodicarboxylate (DIC) (0.14 mL, 0.88 mmol). The resultingmixture was warmed to room temperature over 24 hours. The reactionmixture was cooled to 0° C. and the solid was removed by filtration. Theliquid was concentrated and purified by column (silica) eluting withEtOAc/hexanes (1/1) to afford the BOC-protected product, which wasdissolved in 1,4-dioxane (4 mL) and treated with HCl (4N in 1,4-dioxane1 mL) at room temperature for 4 hours. The solvent was removed undervacuum and the residue was washed with Et₂O (3×2 mL) to give the titlecompound 8 as a HCl-salt (white solid, 300 mg, yield 79%). ¹H NMR (400MHz, CD₃OD): δ 7.90-8.28 (m, 4H, Ar—H), 4.15-4.55 (m, 2H), 3.75-3.95 (m,2H), 3.35-3.45 (m, 0.5H), 3.05-3.15 (m, 0.5H), 2.85-2.95 (m, 0.5H),2.55-2.65 (m, 0.5H), 1.45-2.15 (m, 8H), 0.75-1.15 (m, 10H). LC: 100%;MS: m/z=462 (M+1).

Example 3(2S)N-Cyclopropyl-N-[1-(4-methyl-2-methylaminopentanoyl)-piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide(10)

(2S)N-Cyclopropyl-N-[1-(4-methyl-2-methylaminopentanoyl)-piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide(10) was prepared as follows. A solution of compound 6 (300 mg, 0.78mmol), TEA (0.5 mL), HOBt (100 mg), compound 9 (0.22 g, 0.89 mmol,Fluka), and DCM (4 mL) was cooled with ice-water and treated with DIC(0.14 mL, 0.88 mmol). The resulting mixture was warmed to roomtemperature over 24 hours. The reaction mixture was cooled to 0° C. andthe solid was removed by filtration. The liquid was concentrated andpurified by column (silica) eluting with EtOAc/hexanes (1/1) to affordthe BOC-protected product, which was dissolved in EtOAc (4 mL) andtreated with HCl (2N aqueous, 1 mL) at room temperature for 4 hours. Thesolvent was removed under vacuum and the residue was washed with Et₂O(3×2 mL) to give the desired product 10 as a HCl-salt (white solid, 300mg, yield 75%). ¹H NMR (400 MHz, CD₃OD): δ 7.86-8.26 (m, 4H), 4.35-4.55(m, 2H), 3.75-3.95 (m, 2H), 3.38-3.48 (m, 0.5H), 2.92-3.15 (m, 1H),2.60-2.80 (m, 3.5H, 0.5H+NCH₃), 1.45-2.25 (m, 8H), 0.75-1.20 (m, 10H);LC: 100%; MS: m/z=476 (M+1).

Example 4(2S)N-Cyclopropyl-N-[1-(2-ethylamino-4-methylpentanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide(12)

(2S)N-Cyclopropyl-N-[1-(2-ethylamino-4-methylpentanoyl)-piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide(12) was prepared as follows. A solution of compound 6 (300 mg, 0.78mmol), TEA (0.5 mL), HOBT (100 mg), compound 11 (0.26 g, 0.9 mmol,Chem-Impex), and DCM (4 mL) was cooled with ice-water and treated withDIC (0.14 mL, 0.88 mmol). The resulting mixture was warmed to roomtemperature over 24 hours. The reaction mixture was cooled to 0° C. andthe solid was removed by filtration. The liquid was concentrated andpurified by column (silica) eluting with EtOAc/hexanes (1/1) to affordthe BOC-protected product, which was dissolved in 1,4-dioxane (4 mL) andtreated with HCl (4N in 1,4-dioxane 1 mL) at room temperature for 4hours. The solvent was removed under vacuum, the residue was dissolvedin CHCl₃ (4 mL) and neutralized with NaOH (2N aqueous, 0.5 mL). Theorganic layer was separated and purified by column (silica gel) elutingwith EtOAc/MeOH (10/3) to give the desired product 12, which wasdissolved in 0.2N aqueous HCl (10 mL) and freeze dried to obtain theHCl-salt (200 mg, yield 50%). ¹H NMR (400 MHz, CD₃OD): δ 8.20 (dd, j=7.6& 8.2 Hz, 1H), 8.12 (s, 1H), 8.05 (dd, j=7.6 & 7.7 Hz, 1H), 7.86-7.94(m, 1H), 4.35-4.55 (m, 2H), 3.75-3.95 (m, 2H), 3.38-3.48 (m, 0.5H),2.91-3.19 (m, 3H), 2.59-2.71 (m, 0.5H), 1.35-2.25 (m, 11H), 0.75-1.20(m, 10H); LC: 100%; MS: m/z=490 (M+1).

Example 5(2S)N-[1-(3-Amino-5-methylhexanoyl)piperidin-3-yl]-N-cyclopropyl-3-trifluoromethylbenzenesulfonamide(14)

(2S)N-[1-(3-Amino-5-methylhexanoyl)-piperidin-3-yl]-N-cyclo-propyl-3-trifluoromethylbenzenesulfonamide(14) was prepared as follows. A solution of compound 6 (300 mg, 0.78mmol), TEA (0.5 mL), HOBt (100 mg), compound 13 (0.22 g, 0.89 mmol,Peptech), and DCM (4 mL) was cooled with ice-water and treated with DIC(0.14 mL, 0.88 mmol). The resulting mixture was warmed to roomtemperature over 24 hours. The reaction mixture was cooled to 0° C. andthe solid was removed by filtration. The liquid was concentrated andpurified by column (silica) eluting with EtOAc/hexanes (1/1) to affordthe BOC-protected product, which was dissolved in EtOAc (4 mL) andtreated with HCl (2N aqueous, 1 mL) at room temperature for 4 hours. Thesolvent was removed under vacuum and the residue was washed with Et₂O(3×2 mL) to give the title compound 14 as a HCl-salt (white solid, 250mg, yield 64%). ¹H NMR (400 MHz, CD₃OD): δ 7.66-8.26 (m, 4H), 4.45-4.55(m, 1H), 3.85-3.95 (m, 2H), 3.55-3.65 (m, 1H), 3.28-3.38 (m, 0.5H),2.82-3.05 (m, 2H), 2.48-2.72 (m, 1.5H), 1.45-2.15 (m, 8H), 0.75-1.20 (m,10H); LC: 100%; MS: m/z=476 (M+1).

The following compounds can be similarly prepared:

(2S)N-cyclopropyl-N-[1-(3-methylamino-5-methylhexanoyl)-piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;¹H NMR (400 MHz, CD₃OD): δ 8.02-8.21 (m, 3H), 7.86-7.91 (m, 1H),4.45-4.55 (m, 1H), 3.85-3.95 (m, 2H), 3.45-3.55 (m, 1H), 2.52-3.05 (m,6H), 1.48-2.22 (m, 8H), 0.75-1.35 (m, 11H); LC: 100%; MS: m/z=489 (M+1);and

(2R)N-cyclopropyl-N-[1-(3-methylamino-5-methylhexanoyl)-piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;¹H NMR (400 MHz, CD₃OD): δ 8.02-8.21 (m, 3H), 7.85-7.92 (m, 1H),4.45-4.55 (m, 1H), 3.85-3.95 (m, 2H), 3.45-3.55 (m, 1H), 2.52-3.05 (m,6H), 1.95-2.15 (m, 2H), 1.45-1.85 (m, 6H), 0.75-1.35 (m, 11H); LC:97.8%; MS: m/z=489 (M+1).

Example 6(2S)N-Cyclopropyl-N-{1-[2-(3-methylbutyl)amino-4-methylpentanoyl]piperidin-3-yl}-3-trifluoromethylbenzenesulfonamide(16)

(2S)N-Cyclopropyl-N-{1-[2-(3-methylbutyl)amino-4-methyl-pentanoyl]piperidin-3-yl}-3-trifluoromethylbenzenesulfonamide(16) was prepared as follows. A solution of compound 8 as prepared inExample 2 (100 mg, 0.22 mmol), compound 15 (18 mg, 0.22 mmol, Aldrich)and 4 Å molecular sieves (500 mg) in 2 mL of 1,2-dichloroethane (DCE)was shaken at room temperature for 10 minutes, and then NaB(OAc)₃H (43mg, 0.22 mmol) was charged. The resulting mixture was shaken at roomtemperature for 24 hours. The reaction mixture was quenched with MeOH(0.2 mL), water (2 mL) was added, and the mixture was extracted with DCM(3×4 mL). The organic layers were combined and washed with brine, driedover Na₂SO₃, concentrated under vacuum and purified by column (silicagel, EtOAc, then EtOAc/MeOH 10/1) to give the title compound 16 as freebase, which was converted to its HCl-salt by treating with HCl (1 Naqueous) and drying under vacuum (white solid, 40 mg, yield 34%). ¹H NMR(400 MHz, CD₃OD): δ 8.20 (d, j=7.5 Hz, 1H), 8.12 (s, 1H), 8.06 (dd,j=7.9, 8.1 Hz), 1H), 7.89 (dd, j=7.8, 7.9 Hz, 1H), 4.45-4.55 (m, 2H),3.75-3.95 (m, 2H), 3.45-3.60 (m, 0.5H), 2.55-3.25 (m, 3.5H), 1.45-2.15(m, 11H), 0.75-1.20 (m, 16H); LC: 100%; MS: m/z=532 (M+1).

Example 7(2S)N-Cyclopropyl-N-[1-(2-isopropylamino-4-methylpentanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide(18)

(2S)N-Cyclopropyl-N-[1-(2-isopropylamino-4-methylpentanoyl)-piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide(18) was prepared as follows. A solution of compound 8 prepared inExample 2 (100 mg, 0.22 mmol), compound 17 (12 mg, 0.22 mmol, Aldrich)and 4 Å molecular sieves (500 mg) in 2 mL of 1,2-dichloroethane wasshaken at room temperature for 10 minutes, and then, NaB(OAc)₃H (43 mg,0.22 mmol) was charged. The resulting mixture was shaken at roomtemperature for 24 hours. The reaction mixture was quenched with MeOH(0.2 mL), water (2 mL) was added, and the mixture was extracted with DCM(3×4 mL). The organic layers were combined and then washed with brine,dried over Na₂SO₃, concentrated under vacuum and purified by column(silica gel, EtOAc, then EtOAc/MeOH 10/1) to give the title compound 18as a free base, which was converted to its HCl-salt by treating with HCl(1 N aqueous) and drying under vacuum (white solid, 60 mg, yield 65%).¹H NMR (400 MHz, CD₃OD): δ 8.10-8.22 (m, 2H), 8.06 (dd, j=7.7, 7.8 Hz,1H), 7.91 (dd, j=7.8, 7.9 Hz, 1H), 4.45-4.55 (m, 2H), 3.75-3.95 (m, 2H),3.35-3.45 (m, 1H), 3.3-3.35 (m, 1H), 2.9-2.95 (m, 0.5H), 2.55-2.64 (m,0.5H), 1.35-2.15 (m, 14H), 0.75-1.20 (m, 10H); LC: 100%; MS: m/z=504(M+1).

Example 8(2S)N-Cyclopropyl-N-[1-(2-methylcarbonylpropylamino-4-methylpentanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide(20)

(2S)N-Cyclopropyl-N-[1-(2-methylcarbonylpropylamino-4-methylpentanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide(20) was prepared as follows. A solution of compound 8 prepared inExample 2 (100 mg, 0.22 mmol), compound 19 (12 mg, 0.22 mmol, Aldrich)and 4 Å molecular sieves (500 mg) in 2 mL of 1,2-dichloroethane (DCE)was shaken at room temperature for 10 minutes, and then NaB(OAc)₃H (43mg, 0.22 mmol) was charged. The resulting mixture was shaken at roomtemperature for 24 hours. The reaction mixture was quenched with MeOH(0.2 mL), water (2 mL) was added and the mixture was extracted with DCM(3×4 mL). The organic layers were combined and washed with brine, driedover Na₂SO₃, concentrated under vacuum and purified by column (silicagel, EtOAc, then EtOAc/MeOH 10/1) to give the title compound 20 as whitesolid (40 mg, yield 32%). ¹H NMR (400 MHz, CD₃OD): δ 8.01-8.26 (m, 3H),7.86-7.93 (m, 1H), 5.0-5.15 (m, 0.4H), 4.45-4.55 (m, 1.2H), 3.75-4.35(m, 1.3H), 2.55-3.45 (m, 5H), 0.75-2.20 (m, 26H); LC: 98%; MS: m/z=568(M+Na+).

Example 9N-(4-Fluorophenyl)-2-[3-(3-trifluoromethylbenzenesulfonylamino)-pyrrolidin-1-yl]acetamide(25)

N-(4-Fluorophenyl)-2-[3-(3-trifluoromethylbenzenesulfonylamino)-pyrrolidin-1-yl]acetamide(25) was prepared as follows. A mixture of compound 21 (1.0 g, 5.4 mmol,Aldrich), compound 22 (1 g, 5.4 mmol, Oakwood), and K₂CO₃ (1 g, 7.3mmol) in 10 mL of CH₃CN was shaken at room temperature for 48 hours. Theorganic layer was separated, concentrated and purified by column (Silicagel, EtOAc/hexanes 1/1) to give compound 23 as a white solid (1.5 g),which was dissolved in 4 mL of dioxane, and treated with HCl (4 N indioxane, 4 mL) at room temperature for 12 hours. The solvent was removedunder vacuum to get compound 24 as a white solid (HCl-salt, 1.2 g).Compound 4 (0.16 g, 0.65 mmol) was added to a solution of compound 24(0.2 g, 0.65 mmol) and TEA (0.4 mL) in 2 mL of DCM at room temperature.The resulting mixture was shaken at room temperature for 12 hours. Thereaction mixture was poured on to a column (silica gel, 20 g) and washedwith EtOAc/hexanes (1/1) to give the title compound 25 as a sticky oil,which was converted to its HCl-salt by dissolving in 0.5 mL of dioxaneand then treating with 4N HCl in 1,4-dioxane. The solvent was removedand the salt was dried under vacuum at 50° C. for 24 hours (0.15 g,yield 48%). ¹H NMR (400 MHz, CD₃OD): δ 8.11-8.14 (m, 2H), 7.96 (d, 1H,7.9 Hz), 7.80 (dd, 1H, 7.8 & 8.5 Hz), 7.52-7.56 (m, 2H), 7.01-7.05 (m,2H), 4.21 (s, 2H), 3.5-4.0 (m, 5H), 2.18-2.28 (m, 1H), 1.9-2.0 (m, 1H);LC: 100%; MS: m/z=446 (M+1).

Example 10N-Cyclopropyl-N-(1-{3-[bis-(4-fluorophenyl)amino]propyl}piperidin-3-yl)-3-trifluoromethylbenzenesulfonamide(27)

a) Compound 26 was prepared as follows: A 250-mL round bottom flask wascharged with Pd₂(dba)₃ (100 mg), a ligand (300 mg; Aldrich), and Cs₂CO₃(2.0 g), followed by tert-butanol (25 mL) and 1,4-dioxane (50 mL). Afterthe mixture was stirred for 5 minutes, 4-fluoroaniline (1.0 g, 4.5 mmol)and compound 28 (0.6 g, 5.4 mmol) were added to the flask. The flask wasthen flushed with argon, heated, and stirred at 100° C. for 15 hours.When the reaction was complete, the flask was removed from the heat andallowed to cool to ambient temperature. The residue was concentratedunder vacuum and purified by flash silica column chromatographyisocratically (ethyl acetate/hexanes, 1:9) to give compound 29 as ayellow oil (0.7 g, yield 70%).

b) A 50-mL round bottom flask was charged with compound 29 (0.4 g, 1.95mmol) and compound 30 (0.6 mL, 2.3 mmol; Aldrich) in DMF (6 mL). Themixture was stirred at ambient temperature for 5 minutes, and then NaH(60 mg, 60% in mineral oil) was added. The reaction mixture was heatedto 70° C. for 4 hours. When the reaction was complete, the mixture wasquenched with water (20 mL), transferred to an extraction funnel, andextracted with ethyl acetate (2×20 mL). The organic layers were combinedand dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash silica column chromatography isocratically (ethylacetate/hexanes, 3:100) to give compound 31 as a colorless oil (0.5 g,yield 98%).

c) In a 50 mL vial, compound 31 was re-dissolved in acetonitrile (10 mL)at ambient temperature, and one mL of HF (48% aq.) was added. The vialwas then shaken at ambient temperature for 2 hours. When the reactionwas complete, the reaction mixture was neutralized with 2N aq. NaOH andextracted with ethyl acetate (2×10 mL). The solvents were removed invacuo to leave the product 32 as a colorless oil. The product was usedin the next step without further purification.

d) In a 50-mL vial, the crude product 32 (0.3 g, 1.1 mmol) was dissolvedin DCM (5 mL) and triethylamine (TEA) (0.2 mL). MeSO₂Cl (0.12 mL, 1.5mmol) was added to the reaction mixture and the mixture was shaken atambient temperature for 12 hours. When the reaction was complete, theproduct was purified by flash silica column chromatography isocraticallywith ethyl acetate/hexanes (1:4), to afford compound 26 as a colorlessoil (0.35 g, yield 92%).

N-(1-{3-[Bis-(4-fluorophenyl)amino]propyl}piperidin-3-yl)-N-isopropyl-3-trifluoromethylbenzenesulfonamide(27) was prepared by shaking a mixture of compound 6 (0.2 g, 0.5 mmol),compound 26 (150 mg, 0.44 mmol), TEA (0.2 mL) and K₂CO₃ (1 g, 7.2 mmol)in CH₃CN (2 mL) at 70° C. for 16 hours. After cooling the mixture toroom temperature, the mixture was diluted with DCM (4 mL) and loaded toa column (Silica gel, EtOAc/hexane 3/7) to obtain the title compound 27as a white solid (100 mg, yield 38%). ¹H NMR (400 MHz, CD₃OD): δ 8.15(s, 1H), 8.05 (d, 1H, 7.9 Hz), 7.82 (d, 1H, 7.2 Hz), 7.65 (dd, 1H, 7.8,7.9 Hz), 6.88-7.0 (m, 8H), 3.95-4.0 (m, 1H), 3.65-3.68 (m, 2H),2.75-2.84 (m, 2H), 2.28-2.96 (m, 2H), 1.96-2.05 (m, 2H), 1.52-1.76 (m,7H), 1.04-1.08 (m, 1H), 0.72-0.84 (m, 3H); LC: 100%; MS: m/z=596 (M+1).

Example 11N-Cyclopropyl-N-[1-(3-isobutylaminopropionyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide(35)N-Cyclopropyl-N-[1-(3-isopropylaminopropionyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide(36)N-Cyclopropyl-N-{1-[3-(2-methoxyethylamino)propionyl]piperidin-3-yl}-3-trifluoromethylbenzenesulfonamide(37)N-Cyclopropyl-N-{1-[3-(2-hydroxyethylamino)propionyl]piperidin-3-yl}-3-trifluoromethylbenzenesulfonamide(38)

-   -   ia: isobutylamine; ib: isopropylamine; ic: 2-methoxyethylamine;        id: ethanolamine

General procedure for compounds 35-38: Compound 33 (0.4 g, 4.4 mmol) wasadded to a solution of compound 6 (1.5 g, 3.9 mmol) and TEA (2 mL) inDCM (20 mL) at −20° C. The resulting mixture was warmed to roomtemperature over 2 hours and quenched with water. The organic layer wasseparated, concentrated and purified by column (silica gel,EtOAc/Hexanes 3/7 and 1/1) to obtain compound 34 as an oil (1.1 g, 70%).A mixture of compound 34 (200 mg, 0.5 mmol) and the corresponding amine(ia-id, 1.5 eq, Aldrich) in ETOH (0.5 mL) was heated in a sealed tube at90° C. for 16 hours. After cooling to room temperature, the reactionmixture was diluted with DCM (2 mL) and loaded to a column (silica gel,EtOAc/Hexane 1/1, EtOAc, and EtOAc/MeOH 9/1) to afford the desiredproduct as free base, which was converted to its HCl-salt by treatingwith HCl (1 N aqueous) and drying under vacuum.

N-Cyclopropyl-N-[1-(3-isobutylaminopropionyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide(35) (100 mg, 44%, white solid): ¹H NMR (400 MHz, CD₃OD): δ 8.19 (br,1H), 8.12-8.15 (m, 1H), 8.02-8.07 (m, 1H), 7.85-7.91 (m, 1H), 4.48-4.55(m, 1H), 3.81-3.92 (m, 2H), 3.35 (br, 1H), 2.83-2.94 (m, 5.5H),2.50-2.56 (m, 0.5H), 1.70-2.1 (m, 7H), 0.75-1.18 (m, 10H); LC: 100%; MS:m/z=476 (M+1).

N-Cyclopropyl-N-[1-(3-isopropylaminopropionyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide(36) (60 mg, 25%, white solid): ¹H NMR (400 MHz, CD₃OD): δ 8.17-8.21 (m,1H), 8.14 (br, 1H), 8.01-8.06 (m, 1H), 7.85-7.91 (m, 1H), 4.48-4.54 (m,1H), 3.81-3.92 (m, 2H), 3.41-3.44 (m, 1H), 3.25-3.27 (m, 1H), 2.95-3.02(m, 0.5H), 2.81-2.89 (m, 3H), 2.50-2.52 (m, 0.5H), 1.96-2.12 (m, 2H),1.42-1.82 (m, 3H), 1.37 (d, 6H, 6.6 Hz), 0.8-1.2 (m, 4H); LC: 100%; MS:m/z=462 (M+1).

N-Cyclopropyl-N-{1-[3-(2-methoxyethylamino)propionyl]piperidin-3-yl}-3-trifluoromethylbenzenesulfonamide(37) (90 mg, 38%, white solid): ¹H NMR (400 MHz, CD₃OD): δ 8.18-8.21 (m,1H), 8.12-8.15 (m, 1H), 8.01-8.06 (m, 1H), 7.86-7.91 (m, 1H), 4.48-4.54(m, 1H), 3.81-3.92 (m, 2H), 3.65-3.71 (m, 2H), 3.43-3.47 (m, 3H),3.25-3.32 (m, 4H), 2.94-3.02 (m, 0.5H), 2.82-2.90 (m, 3H), 2.48-2.57 (m,0.5H), 1.95-2.11 (m, 2H), 1.42-1.82 (m, 3H), 0.8-1.2 (m, 4H); LC: 100%;MS: m/z=478 (M+1).

N-Cyclopropyl-N-{1-[3-(2-hydroxyethylamino)propionyl]-piperidin-3-yl}-3-trifluoromethylbenzenesulfonamide(38) (150 mg, 62%, white solid): ¹H NMR (400 MHz, CD₃OD): δ 8.21 (dd,1H, 7.0 & 7.9 Hz), 8.16 (d, 1H, 8.6 Hz), 8.04 (dd, 1H, 7.8 & 8.2 Hz),7.86-7.91 (m, 1H), 4.48-4.54 (m, 1H), 3.81-3.92 (m, 4H), 3.34-3.39 (m,2H), 3.18-3.22 (m, 2H), 2.94-3.02 (m, 0.5H), 2.82-2.92 (m, 3H),2.50-2.57 (m, 0.5H), 1.95-2.11 (m, 2H), 1.42-1.82 (m, 3H), 0.8-1.2 (m,4H); LC: 100%; MS: m/z=464 (M+1).

Example 12N-Cyclopropyl-N-[1-(2-isobutylaminoacetyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide(41)

N-Cyclopropyl-N-[1-(2-isobutylaminoacetyl)piperidin-3-yl]-3-trifluoromethyl-benzenesulfonamide(41) was prepared as follows. Compound 39 (0.6 g, 5.4 mmol, Aldrich) wasadded to a solution of compound 6 (1.5 g, 3.9 mmol) and TEA (2 mL) inDCM (20 mL) at room temperature over 10 minutes. The reaction was thenquenched with water (4 mL) and the organic layer was separated,concentrated and purified by column (silica gel, EtAOc/hexanes 1/1) togive compound 40 as a colorless oil (1.2 g, 70%).

A mixture of compound 40 (100 mg, 0.24 mmol), isobutylamine (ia,Aldrich, 70 mg, 2.0 eq.) and TEA (1 mL) in DMF (1 mL) was shaken at 75°C. for 10 hours. After cooling to room temperature, the reaction mixturewas purified by column (silica gel, DCM/MeOH 100/15) to give the titlecompound 41 as a free base (100 mg, 48%, white solid). ¹H NMR (400 MHz,CDCl₃): δ 8.14 (d, 1H, 11.9 Hz), 8.09 (dd, 1H, 8.7 & 9.2 Hz), 7.88 (dd,1H, 7.8 & 8.2 Hz), 7.72 (dd, 1H, 7.7 & 7.9 Hz), 4.48-4.54 (m, 1H),3.68-3.82 (m, 2H), 3.42-3.52 (m, 2H), 3.08-3.15 (m, 0.5H), 2.78-2.9 (m,1H), 2.38-2.48 (m, 2.5H), 1.75-2.08 (m, 5H), 1.42-1.82 (m, 2H), 0.96 (d,6H, 6.6 Hz), 0.88-0.92 (m, 1H), 0.74-0.82 (m, 3H); LC: 100%; MS: m/z=462(M+1).

Example 132-{3-[Cyclopropyl-(3-trifluoromethylbenzenesulfonyl)-amino]-piperidin-1-yl}-N-isobutyl-acetamide(42)2-{3-[Cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-N-(4-fluorophenyl)-acetamide(43)

La: 2-Chloro-N-isobutyl-acetamide (prepared as shown below); Lb:2-Chloro-N-(4-fluorophenyl)-acetamide (Oakwood)

General procedure for preparing compounds 42 and 43: A mixture ofcompound 6 (100 mg, 0.26 mmol), compound La or Lb (0.3 mmol) and K₂CO₃(200 mg) in DMF (1 mL) was shaken at 40° C. for 16 hours. After coolingto room temperature, the reaction mixture was quenched with water,extracted with CHCl₃, concentrated and purified by column (silica gel,EtOAc/hexanes 1/1) to give the desired product as a free base. The freebase was converted to its HCl-salt by treating with HCl (1 N aqueous)and drying under vacuum.

2-Chloro-N-isobutyl-acetamide (La) was prepared by adding compound 39(1.2 g, 17.8 mmol, 1.2 eq.) to a solution of isobutylamine (1.6 g, 1.0eq., Aldrich) and TEA (2 mL) in DCM (20 mL) at 0° C. The reactionmixture was warmed to room temperature over 3 hours and then quenchedwith water (6 mL), washed with brine (4 mL), concentrated and purifiedby column (silica gel, EtOAc/hexanes 1/9) to give compound La as acolorless oil (2 g, 62%).

2-{3-[Cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-N-isobutyl-acetamide(42) (100 mg, 83%, white solid): ¹H NMR (400 MHz, CD₃OD): δ 8.22 (d, 1H,8.1 Hz), 8.18 (s, 1H), 8.07 (d, 1H, 7.9 Hz), 7.91 (dd, 1H, 7.8 & 7.9Hz), 4.32-4.39 (m, 1H), 4.02 (s, 2H), 3.53-3.60 (m, 2H), 3.36-3.42 (m,1H), 3.02-3.12 (m, 3H), 1.98-2.1 (m, 3H), 1.65-1.88 (m, 3H), 1.04-1.09(m, 1H), 0.95 (d, 6H, 6.6 Hz), 0.84-0.92 (m, 3H); LC: 100%; MS: m/z=462(M+1).

2-{3-[Cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-N-(4-fluorophenyl)acetamide(43) (120 mg, 92%, off-white solid, free base): ¹H NMR (400 MHz, CDCl₃):δ 9.0 (br, 1H, NH), 8.15 (s, 1H), 8.03 (d, 1H, 7.9 Hz), 7.83 (d, 1H, 7.9Hz), 7.55-7.61 (m, 3H), 7.03-7.07 (m, 2H), 4.02-4.19 (m, 1H), 3.13-3.21(m, 2H), 2.88-2.96 (m, 2H), 2.46-2.54 (m, 1H), 2.14-2.21 (m, 1H),1.96-1.99 (m, 1H), 1.79-1.83 (m, 1H), 1.63-1.71 (m, 3H), 1.04-1.09 (m,1H), 0.74-0.85 (m, 3H); LC: 100%; MS: m/z=500 (M+1).

Example 14N-Cyclopropyl-N-{1-[2-(4-methoxybenzylamino)acetyl]-piperidin-3-yl}-3-trifluoromethylbenzenesulfonamide(44)N-Cyclopropyl-N-(1-{2-[(pyridin-3-ylmethyl)amino]acetyl}-piperidin-3-yl)-3-trifluoromethylbenzenesulfonamide(45)

Compound 40 was prepared as shown in Example 12. Compound 44 wasprepared as follows. A mixture of compound 40 (100 mg, 0.24 mmol),4-methoxy-benzylamine (ie, Aldich, 70 mg, 2.0 eq.) and TEA (1 mL) in DMF(1 mL) was shaken at 75° C. for 10 hours. After cooling to roomtemperature, the reaction mixture was purified by column (silica gel,DMC/MeOH 100/15) to give the title compound 44 as a free base (yield70%, white solid). ¹H NMR (400 MHz, CD₃OD, HCl-salt): δ 8.12 (d, 1H, 7.7Hz), 8.14 (s, 1H), 8.02-8.06 (m, 1H), 7.86-7.91 (m, 1H), 7.42-7.5 (m,2H), 7.02-7.05 (m, 2H), 4.42-4.48 (m, 1H), 4.0-4.22 (m, 4H), 3.8-3.85(m, 4H), 3.68-3.72 (m, 1H), 2.9-3.0 (m, 1.5H), 2.58-2.62 (m, 0.5H),1.96-2.1 (m, 2H), 1.45-1.85 (m, 3H), 0.8-1.1 (m, 4H); LC: 100%; MS:m/z=526 (M+1).

N-Cyclopropyl-N-(1-{2-[(pyridin-3-ylmethyl)amino]acetyl}-piperidin-3-yl)-3-trifluoromethylbenzenesulfonamide(45) was prepared accordingly using 3-(aminomethyl)pyridine (if,Aldrich). The title compound 45 was obtained as a free base (yield 40%,white solid). ¹H NMR (400 MHz, CD₃OD, HCl-salt): δ 9.14-9.18 (m, 1H),8.98-9.03 (m, 1H), 8.86-8.9 (m, 1H), 8.04-8.24 (m, 4H), 7.86-7.92 (m,1H), 4.58-4.63 (m, 2H), 4.18-4.42 (m, 3H), 3.68-3.85 (m, 2H), 2.9-3.0(m, 1.5H), 2.58-2.72 (m, 0.5H), 1.96-2.1 (m, 2H), 1.45-1.85 (m, 3H),0.8-1.1 (m, 4H); LC: 100%; MS: m/z=497 (M+1).

Example 15

Compounds of the invention have been tested in the calcium mobilizationand/or electrophysiological assay for N-type calcium channel blockingactivity, which are described in detail above. Some compounds describedhave also been tested in the calcium mobilization assay for L-typecalcium channel blocking activity, which is described in detail above.Representative values are presented in TABLE 2.

TABLE 2 Evaluation of the tested compounds as N-type calcium channel(NTCC) blockers and L-type calcium channel (LTCC) blockers after acalcium mobilization in vitro assay NTCC LTCC COMPOUND IC₅₀ (μM) IC₅₀(μM) (2S) N-[1-(2-amino-4- 1.10 6.58 methylpentanoyl)piperidin-3-yl]-N-cyclopropyl-3-trifluoromethylbenzene- sulfonamide (2S)N-cyclopropyl-N-[1-(2-ethylamino-4- 0.13 5.07methylpentanoyl)piperidin-3-yl]-3- trifluoromethyl-benzenesulfonamide(2S) N-cyclopropyl-N-[1-(4-methyl-2- 0.54 6.58methylaminopentanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide (2S) N-[1-(3-amino-5- 0.28 0.50methylhexanoyl)piperidin-3-yl]-N- cyclopropyl-3-trifluoromethylbenzene-sulfonamide (2S) N-cyclopropyl-N-[1-(2- 0.51 NDmethylcarbonylpropyl-amino-4- methylpentanoyl)-piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide (2S) N-cyclopropyl-N-{1-[2-(3- 0.36 NDmethylbutyl)amino-4- methylpentanoyl]piperidin-3-yl}-3-triluoro-methylbenzenesulfonamide (2S) N-cyclopropyl-N-[1-(2-isopropylamino- 0.21ND 4-methylpentanoyl)piperidin-3-yl]-3-triluoromethyl-benzenesulfonamide N-cyclopropyl-N-(1-{3-[bis-(4- 2.22 NDfluorophenyl)amino]propyl}-piperidin-3-yl)-3-trifluoromethyl-benzenesulfonamide N-cyclopropyl-N-[1-(3- 0.82 5.63isobutylaminopropionyl)-piperidin-3-yl]-3-trifluoromethyl-benzenesulfonamide N-cyclopropyl-N-[1-(3- 0.63 8.77isopropylaminopropionyl)-piperidin-3-yl]-3-trifluoromethyl-benzenesulfonamide N-cyclopropyl-N-{1-[3-(2- 0.81 10~20methoxyethylamino)-propionyl]-piperidin-3-yl}-3-trifluoromethyl-benzenesulfonamide N-cyclopropyl-N-{1-[3-(2- 2.83ND hydroxyethylamino)-propionyl]-piperidin-3-yl}-3-trifluoromethyl-benzenesulfonamide N-cyclopropyl-N-[1-(2- 0.695.75 isobutylaminoacetyl)-piperidin-3-yl]-3-trifluoromethylbenzene-sulfonamide 2-{3-[cyclopropyl-(3-trifluoromethyl-0.43 9.82 benzenesulfonyl)amino]piperidin-1-yl}-N- isobutyl-acetamide2-{3-[cyclopropyl-(3- 0.36 6.18 trifluoromethylbenzene-sulfonyl)amino]piperidin-1-yl}-N-(4- fluorophenyl)-acetamideN-(4-fluorophenyl)-2-[3- 1.68 ND trifluoromethylbenzene-sulfonamino)pyrrolidin-1-yl]acetamide N-cyclopropyl-N-{1-[2-(4- 0.424.65 methoxybenzylamino)-acetyl]-piperidin-3-yl}-3-trifluoromethyl-benzenesulfonamideN-cyclopropyl-N-(1-{2-[(pyridin-3- 1.20 >20   ylmethyl)-amino]acetyl}-piperidin-3-yl)-3-trifluoromethyl-benzenesulfonamide ND = not determined

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the invention or anyembodiment thereof.

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

All patents and publications cited herein are fully incorporated byreference herein in their entirety.

1. A compound having the Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein: R¹ and R² are each independently selected from the groupconsisting of hydrogen, alkyl, haloalkyl, halogen, alkoxy, haloalkoxy,cyano, nitro, amino, aminoalkyl, alkylamino, dialkylamino, and hydroxy;R³ is selected from the group consisting of hydrogen, alkyl, alkenyl,cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylalkyl,3-tetrahydrofuranylalkyl, alkylsulfonylaminoalkyl, aminocarbonylalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cyanoalkyl,carboxyalkyl, and alkoxycarbonylalkyl; Z is Z¹, wherein Z¹ is

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen; alkyl; alkenyl; hydroxyalkyl; haloalkyl; mercaptoalkyl;aminoalkyl; alkylaminoalkyl; dialkylaminoalkyl; alkoxyalkyl;aminocarbonylalkyl; cycloalkyl; and phenyl optionally substituted withone or more substituents independently selected from the groupconsisting of alkyl, cycloalkyl, halogen, cyano, amino, alkylamino,dialkylamino, hydroxy, nitro, haloalkyl, and alkoxy; or R⁴ is selectedfrom the group consisting of hydrogen, alkyl, alkenyl, hydroxyalkyl,haloalkyl, mercaptoalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, alkoxyalkyl, aminocarbonylalkyl, cycloalkyl, andphenyl optionally substituted with one or more substituentsindependently selected from the group consisting of alkyl, cycloalkyl,halogen, cyano, amino, alkylamino, dialkylamino, hydroxy, nitro,haloalkyl, and alkoxy, and R⁵ is selected from the group consisting ofhydroxyalkyl optionally substituted at one or more carbon atoms withoptionally substituted aryl or optionally substituted benzyl;aminoalkyl; dialkylaminoalkyl; diaminoalkyl; alkoxyalkyl;aminocarbonylalkyl; cycloalkyl; alkyl optionally substituted with one ortwo substituents each independently selected from the group consistingof optionally substituted cycloalkyl, optionally substituted phenyl,optionally substituted benzyl, optionally substituted benzyloxy,optionally substituted heteroaryl, and optionally substitutedheterocyclo; optionally substituted heteroaryl; R¹⁶—C(O)—; and R¹⁶—SO₂—,wherein R¹⁶ is selected from the group consisting of alkyl, alkoxy,optionally substituted cycloalkyl, optionally substituted aryl,optionally substituted benzyl, and 1,2,3,4-tetrahydroquinolinyl or1,2,3,4-tetrahydroisoquinolinyl optionally substituted at the nitrogenatom with alkylcarbonyl or haloalkylcarbonyl; or R⁴ and R⁵ together withthe nitrogen atom to which they are attached form a 5- or 6-memberedheterocyclic ring wherein one or more carbon atoms of the heterocyclicring are optionally replaced with NR¹⁷, O, or S, wherein R¹⁷ is hydrogenor C₁₋₃ alkyl; R⁶ and R⁷ are each independently selected from the groupconsisting of hydrogen; alkyl; alkenyl; alkynyl; hydroxyalkyl;alkoxyalkyl; haloalkyl; aminoalkyl; cycloalkyl, wherein one or morecarbon atoms are optionally replaced with NR¹⁷, O, S, or SO₂, whereinR¹⁷ is hydrogen or C₁₋₃ alkyl, to form a heterocyclic ring;bicycloalkyl; cycloalkylalkyl, wherein one or more carbon atoms areoptionally replaced with NR¹⁷, O, S, or SO₂, wherein R¹⁷ is hydrogen orC₁₋₃ alkyl, to form a heterocyclic ring; phenyl optionally substitutedwith one or two substituents independently selected from the groupconsisting of alkyl, cycloalkyl, halogen, cyano, amino, alkylamino,dialkylamino, hydroxy, nitro, haloalkyl, and alkoxy; benzyl optionallysubstituted with one or two substituents independently selected from thegroup consisting of alkyl, cycloalkyl, halogen, cyano, amino,alkylamino, dialkylamino, hydroxy, nitro, haloalkyl, and alkoxy;benzyloxyalkyl; benzyloxybenzyl; naphthylmethyl; heteroaryl optionallysubstituted with one or two substituents independently selected from thegroup consisting of alkyl, cycloalkyl, halogen, cyano, amino,alkylamino, dialkylamino, hydroxy, nitro, haloalkyl, and alkoxy; andheteroarylalkyl optionally substituted with one or two substituentsindependently selected from the group consisting of alkyl, cycloalkyl,halogen, cyano, amino, alkylamino, dialkylamino, hydroxy, nitro,haloalkyl, and alkoxy; provided that when either R⁴ or R⁵ is cycloalkyland y is 0, then at least one of R⁶ and R⁷ is other than hydrogen; or R⁶and R⁷ together form benzylidenyl optionally substituted with one or twosubstituents independently selected from the group consisting of alkyl,cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino, hydroxy,nitro, haloalkyl, and alkoxy; or R⁶ and R⁷ together with the carbon atomto which they are attached form a saturated or unsaturated C₃₋₇cycloalkyl ring optionally substituted with one or more substituentseach independently selected from the group consisting of hydroxy, amino,carboxy, alkoxycarbonyl, alkylamino, dialkylamino, and ═O, wherein oneor more carbon atoms of the C₃₋₇ cycloalkyl ring are optionally replacedwith NR¹⁷, O, S or SO₂, wherein R¹⁷ is hydrogen or C₁₋₃ alkyl, to form aheterocyclic ring; or wherein two adjacent carbon atoms of the C₃₋₇cycloalkyl ring can form a bridge —O— to form a bicyclic ring; orwherein one carbon atom of the C₃₋₇ cycloalkyl ring is linked to aheterocyclic ring to form a spirocyclic ring; R⁷ is hydrogen; R⁴ ishydrogen, alkyl, or hydroxyalkyl; and R⁵ and R⁶ together form a bridge—CH₂—CH₂—CH₂— or —CH₂—CHG¹-CHG²-CH₂—, wherein G¹ and G² are bothhydrogen or together with the carbon atoms to which they are attachedform a fused phenyl group; R³² are R³³ are each independently selectedfrom the group consisting of hydroxy, alkyl, hydroxyalkyl, haloalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, and alkoxyalkyl; or R³³is hydrogen and R³² is hydroxy, alkyl, hydroxyalkyl, haloalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or alkoxyalkyl; or R³²and R³³ together with the carbon atom to which they are attached form aC₃₋₇ cycloalkyl ring; or R³² and R⁴ together with the carbon andnitrogen atoms to which they are attached, respectively, form a 4-, 5-or 6-membered heterocyclic ring optionally substituted with one or moresubstituents each independently selected from the group consisting ofhydroxy, hydroxyalkyl, alkyl, amino, alkylamino, dialkylamino, carboxy,and alkoxycarbonyl; R³³ is hydrogen, hydroxy, alkyl, hydroxyalkyl,haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, oralkoxyalkyl; and R⁵, R⁶ and R⁷ are each independently selected from thegroup consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,haloalkyl, aminoalkyl, carboxy, and alkoxycarbonyl; x is 0 or 1; y is 0or 1; m is 0, 1, 2 or 3; and q is 0, 1, 2, or 3; with the followingprovisos: 1) when q is 1, m and y are 0, R³ is cyclohexyl, R⁴, R⁵ and R⁶are each hydrogen, and R⁷ is benzyl substituted with chlorine at thepara-position, then R¹ and R² are not both hydrogen; 2) when q is 1, mand y are 0, R³ is cyclohexyl, R⁴ and R⁶ are each hydrogen, R isalkoxycarbonyl, and R⁷ is benzyl substituted with chlorine at thepara-position, then R¹ and R² are not both hydrogen.
 2. The compound ofclaim 1, having the Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein: R¹ and R² are each independently selected from the groupconsisting of hydrogen, alkyl, haloalkyl, halogen, alkoxy, haloalkoxy,cyano, nitro, amino, aminoalkyl, alkylamino, dialkylamino, and hydroxy;R³ is selected from the group consisting of alkyl, alkenyl, cycloalkyl,cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydrofuranylalkyl, 3-tetrahydrofuranylalkyl,alkylsulfonylaminoalkyl, aminocarbonylalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, cyanoalkyl, carboxyalkyl, andalkoxycarbonylalkyl; Z is Z¹, wherein Z¹ is

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen; alkyl; alkenyl; hydroxyalkyl; haloalkyl; mercaptoalkyl;aminoalkyl; alkylaminoalkyl; dialkylaminoalkyl; alkoxyalkyl; and phenyloptionally substituted with one or more substituents independentlyselected from the group consisting of alkyl, cycloalkyl, halogen, cyano,amino, alkylamino, dialkylamino, hydroxy, nitro, haloalkyl, and alkoxy;or R⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl,hydroxyalkyl, haloalkyl, mercaptoalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, alkoxyalkyl, and phenyl optionally substituted withone or more substituents independently selected from the groupconsisting of alkyl, cycloalkyl, halogen, cyano, amino, alkylamino,dialkylamino, hydroxy, nitro, haloalkyl, and alkoxy, and R⁵ is selectedfrom the group consisting of hydroxyalkyl optionally substituted at oneor more carbon atoms with optionally substituted aryl or optionallysubstituted benzyl; aminoalkyl; dialkylaminoalkyl; diaminoalkyl;alkoxyalkyl; alkyl optionally substituted with one or two substituentseach independently selected from the group consisting of optionallysubstituted cycloalkyl, optionally substituted phenyl, optionallysubstituted benzyl, optionally substituted heteroaryl, and optionallysubstituted heterocyclo; optionally substituted heteroaryl; R¹⁶—C(O)—;and R⁶—SO₂—, wherein R¹⁶ is selected from the group consisting of alkyl,alkoxy, optionally substituted cycloalkyl, optionally substituted aryl,optionally substituted benzyl, and 1,2,3,4-tetrahydroquinolinyl or1,2,3,4-tetrahydroisoquinolinyl optionally substituted at the nitrogenatom with alkylcarbonyl or haloalkylcarbonyl; or R⁴ and R⁵ together withthe nitrogen atom to which they are attached form a 5- or 6-memberedheterocyclic ring wherein one or more carbon atoms of the heterocyclicring are optionally replaced with NR¹⁷, O, or S, wherein R is hydrogenor C₁₋₃ alkyl; R⁶ and R⁷ are each independently selected from the groupconsisting of hydrogen; alkyl; hydroxyalkyl; alkoxyalkyl; haloalkyl;aminoalkyl; cycloalkyl; phenyl optionally substituted with one or twosubstituents independently selected from the group consisting of alkyl,cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino, hydroxy,nitro, haloalkyl, and alkoxy; benzyl optionally substituted with one ortwo substituents independently selected from the group consisting ofalkyl, cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino,hydroxy, nitro, haloalkyl, and alkoxy; benzyloxyalkyl; heteroaryloptionally substituted with one or two substituents independentlyselected from the group consisting of alkyl, cycloalkyl, halogen, cyano,amino, alkylamino, dialkylamino, hydroxy, nitro, haloalkyl, and alkoxy;and heteroarylalkyl optionally substituted with one or two substituentsindependently selected from the group consisting of alkyl, cycloalkyl,halogen, cyano, amino, alkylamino, dialkylamino, hydroxy, nitro,haloalkyl, and alkoxy; or R⁶ and R⁷ together with the carbon atom towhich they are attached form a C₃₋₇ cycloalkyl ring optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of hydroxy, amino, carboxy, alkoxycarbonyl,alkylamino, dialkylamino, and ═O, wherein one or more carbon atoms ofthe C₃₋₇ cycloalkyl ring are optionally replaced with NR¹⁷ or O, whereinR¹⁷ is hydrogen or C₁₋₃ alkyl, to form a heterocyclic ring; or whereintwo adjacent carbon atoms of the C₃₋₇ cycloalkyl ring can form a bridge—O— to form a bicyclic ring; or wherein one carbon atom of the C₃₋₇cycloalkyl ring is linked to a heterocyclic ring to form a spirocyclicring; R⁷ is hydrogen; R⁴ is hydrogen, alkyl, or hydroxyalkyl; and R⁵ andR⁶ together form a bridge —CH₂—CH₂—CH₂— or —CH₂—CHG¹-CHG²-CH₂—, whereinG¹ and G² are both hydrogen or together with the carbon atoms to whichthey are attached form a fused phenyl group; R³² are R³³ are eachindependently selected from the group consisting of hydroxy, alkyl,hydroxyalkyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,and alkoxyalkyl; or R³³ is hydrogen and R³² is hydroxy, alkyl,hydroxyalkyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,or alkoxyalkyl; or R³² and R³³ together with the carbon atom to whichthey are attached form a C₃₋₇ cycloalkyl ring; or R³² and R⁴ togetherwith the carbon and nitrogen atoms to which they are attached,respectively, form a 5- or 6-membered heterocyclic ring optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of hydroxy, hydroxyalkyl, alkyl, amino,alkylamino, dialkylamino, carboxy, and alkoxycarbonyl; R³³ is hydrogen,hydroxy, alkyl, hydroxyalkyl, haloalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, or alkoxyalkyl; and R⁵, R⁶ and R⁷ are eachindependently selected from the group consisting of hydrogen, alkyl,hydroxyalkyl, alkoxyalkyl, haloalkyl, aminoalkyl, carboxy, andalkoxycarbonyl; x is 0 or 1; y is 0 or 1; m is 0, 1, 2 or 3; and q is 0,1, 2, or 3; with the following proviso: when q is 1, m is 0, R³ iscyclohexyl, R⁴, R⁵ and R⁶ are each hydrogen, and R⁷ is benzylsubstituted with chlorine at the para-position, then R¹ and R² are notboth hydrogen.
 3. The compound of claim 1, wherein R³ is selected fromthe group consisting of methyl, ethyl, iso-pentyl, iso-butyl,iso-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl,cyclopropylethyl, methoxymethyl, methoxyethyl, hydroxymethyl,hydroxyethyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,2-tetrahydrofuranylethyl, methylsulfonamidomethyl,methylsulfonamidoethyl, aminocarbonylmethyl, and aminocarbonylethyl. 4.The compound of claim 1, wherein q is
 2. 5. The compound of claim 1,having the Formula II:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof. 6.The compound of claim 1, wherein R¹ and R² are each independentlyselected from the group consisting of hydrogen, halogen, alkyl,haloalkyl, cyano, alkoxy, haloalkoxy, nitro, amino, alkylamino, anddialkylamino.
 7. The compound of claim 6, wherein R¹ is hydrogen and R²is trifluoromethyl, or R¹ and R² are both hydrogen.
 8. The compound ofclaim 1, having the Formula III:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof. 9.The compound of claim 1, having the Formula V:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof. 10.The compound of claim 9, wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen, alkyl, hydroxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl,unsubstituted phenyl, and phenyl substituted with one or twosubstituents independently selected from the group consisting of alkyl,cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino, hydroxy,nitro, haloalkyl, and alkoxy.
 11. The compound of claim 9, wherein R⁴and R⁵ together with the nitrogen atom to which they are attached form a5- or 6-membered heterocyclic ring wherein one or more carbon atoms ofthe heterocyclic ring are optionally replaced with NR¹⁷, O, or S,wherein R¹⁷ is hydrogen or C₁₋₃ alkyl.
 12. The compound of claim 9,wherein R⁵ is R¹⁶—C(O)—, wherein R¹⁶ is alkyl, cycloalkyl, or phenylunsubstituted or substituted with one or two substituents independentlyselected from the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, amino, alkylamino, and dialkylamino.
 13. The compound ofclaim 9, wherein R⁵ is R¹⁶—SO₂—, wherein R¹⁶ is alkyl, phenylunsubstituted or substituted with one or two substituents independentlyselected from the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, amino, alkylamino, dialkylamino, and alkylcarbonylamino, or1,2,3,4-tetrahydroquinolinyl or 1,2,3,4-tetrahydroisoquinolinyloptionally substituted at the nitrogen atom with alkylcarbonyl orhaloalkylcarbonyl.
 14. The compound of claim 9, wherein R⁵ is selectedfrom the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, and alkoxyalkyl.
 15. The compound of claim 9, whereinR⁶ is hydrogen and R⁷ is methyl; propyl; iso-propyl; butyl; tert-butyl;sec-butyl; iso-butyl; hydroxymethyl; 1-hydroxyethyl; unsubstitutedphenyl; phenyl substituted with one or two substituents independentlyselected from the group consisting of methyl ethyl, propyl, iso-propyl,butyl, tert-butyl, halogen, cyano, amino, methylamino, dimethylamino,hydroxy, nitro, and trifluoromethyl; unsubstituted benzyl; benzylsubstituted with one or two substituents independently selected from thegroup consisting of methyl ethyl, propyl, iso-propyl, butyl, tert-butyl,halogen, cyano, amino, methylamino, dimethylamino, hydroxy, nitro, andtrifluoromethyl; 1-benzyloxyethyl; cyclopentyl; cyclohexyl;cyclopentylmethyl; or cyclohexylmethyl.
 16. The compound of claim 9,wherein R⁶ is hydrogen, R⁷ is alkyl, and R⁴ and R⁵ are independentlyhydrogen, alkyl, or hydroxyalkyl, or R⁴ and R⁵ together with thenitrogen atom to which they are attached form a 5- or 6-memberedheterocyclic ring wherein one or more carbon atoms of the heterocyclicring are optionally replaced with NR¹⁷, O, or S, wherein R¹⁷ is hydrogenor C₁₋₃ alkyl.
 17. The compound of claim 9, wherein R⁶ and R⁷ togetherwith the carbon atom to which they are attached form cyclopentyl orcyclohexyl.
 18. The compound of claim 9, wherein R⁷ is hydrogen; R⁴ ishydrogen, alkyl, or hydroxyalkyl; and R⁵ and R⁶ together form a bridge—CH₂—CH₂—CH₂— or —CH₂—CHG¹-CHG²-CH₂—, wherein G¹ and G² are bothhydrogen or together with the carbon atoms to which they are attachedform a fused phenyl group.
 19. The compound of claim 9, wherein theconfiguration at the carbon atom to which —NR⁴R⁵ is attached is (S). 20.The compound of claim 9, having the Formula VI:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein: R⁴¹ and R⁵¹ and are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, hydroxyalkyl, haloalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, and alkoxyalkyl; and R¹⁸and R¹⁹ and are each independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, halogen, cyano, amino, alkylamino,dialkylamino, hydroxy, nitro, haloalkyl, and alkoxy.
 21. The compound ofclaim 20, wherein R⁴¹ and R⁵¹ are each independently selected from thegroup consisting of hydrogen, alkyl, and hydroxyalkyl.
 22. The compoundof claim 20, wherein R⁴¹ and R⁵¹ both are hydrogen, or R⁴¹ is hydrogenand R⁵¹ is C₁₋₃ alkyl.
 23. The compound of claim 20, wherein R¹⁸ and R¹⁹are each independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, C₃₋₆ cycloalkyl, halogen, cyano, amino, C₁₋₃ alkylamino,di(C₁₋₃)alkylamino, hydroxy, nitro, halo(C₁₋₆)alkyl, and C₁₋₆ alkoxy.24. The compound of claim 9, having the Formula VII:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein: R⁴² and R⁵² and are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, hydroxyalkyl, haloalkyl,mercaptoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, andalkoxyalkyl; or R⁴² and R⁵² together with the nitrogen atom to whichthey are attached form a 5- or a 6-membered heterocyclic ring whereinone or more carbon atoms of the heterocyclic ring are optionallyreplaced with NR¹⁷, O or S, wherein R¹⁷ is hydrogen or C₁₋₃ alkyl; andR²⁰ and R²¹ are independently H or CH₃.
 25. The compound of claim 24,wherein R⁴² and R⁵² are each independently selected from the groupconsisting of hydrogen, methyl, ethyl, hydroxymethyl, and hydroxyethyl.26. The compound of claim 24, wherein R⁴² and R⁵² together with thenitrogen atom to which they are attached form a 5- or 6-memberedheterocyclic ring selected from the group consisting of oxazolidinyl,isoxazolidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl,hexahydropyrimidinyl, piperidinyl, piperazinyl, 4-methylpiperazinyl,morpholinyl, thiomorpholinyl, and tetrahydropyridyl.
 27. The compound ofclaim 24, wherein R⁴² and R⁵² are independently hydrogen, methyl orhydroxyethyl; or R⁴² and R⁵² together with the nitrogen atom to whichthey are attached form 1-pyrrolidinyl, 4-thiomorpholinyl, or4-methylpiperazinyl.
 28. The compound of claim 24, wherein R²⁰ and R²¹are both H when R⁴² and R⁵² together form the 5- or 6-memberedheterocyclic ring.
 29. The compound of claim 24, wherein R⁴² and R⁵² areboth hydrogen or R⁴² is hydrogen and R⁵² is alkyl.
 30. The compound ofclaim 24, wherein m is
 1. 31. The compound of claim 1 selected from thegroup consisting of:N-[1-(2-amino-4-methylpentanoyl)piperidin-3-yl]-N-cyclopropyl-3-trifluoromethylbenzenesulfonamide;N-cyclopropyl-N-[1-(4-methyl-2-methylaminopentanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;N-cyclopropyl-N-[1-(2-ethylamino-4-methylpentanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;N-[1-(3-amino-5-methylhexanoyl)piperidin-3-yl]-N-cyclopropyl-3-trifluoromethylbenzenesulfonamide;N-cyclopropyl-N-[1-(2-methylcarbonylpropylamino-4-methyl-pentanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;N-cyclopropyl-N-{1-[2-(3-methylbutyl)amino-4-methyl-pentanoyl]-piperidin-3-yl}-3-trifluoromethylbenzenesulfonamide;N-cyclopropyl-N-[1-(2-isopropylamino-4-methylpentanoyl)-piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;N-cyclopropyl-N-[1-(3-methylamino-5-methylhexanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;N-cyclopropyl-N-[1-(3-isobutylaminopropionyl)-piperidin-3-yl]-3-trifluoromethyl-benzenesulfonamide;N-cyclopropyl-N-[1-(3-isopropylaminopropionyl)-piperidin-3-yl]-3-trifluoromethyl-benzenesulfonamide;N-cyclopropyl-N-{1-[3-(2-methoxyethylamino)-propionyl]-piperidin-3-yl}-3-trifluoromethyl-benzenesulfonamide;N-cyclopropyl-N-{1-[3-(2-hydroxyethylamino)-propionyl]-piperidin-3-yl}-3-trifluoromethyl-benzenesulfonamide;N-cyclopropyl-N-[1-(2-isobutylaminoacetyl)-piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;N-cyclopropyl-N-{1-[2-(4-methoxybenzylamino)acetyl]-piperidin-3-yl}-3-trifluoromethylbenzenesulfonamide;N-cyclopropyl-N-(1-{2-[(pyridin-3-ylmethyl)amino]acetyl}-piperidin-3-yl)-3-trifluoromethylbenzenesulfonamide;or a pharmaceutically acceptable salt, prodrug or solvate thereof. 32.The compound of claim 1 selected from the group consisting of:(2S)N-[1-(2-amino-4-methylpentanoyl)piperidin-3-yl]-N-cyclopropyl-3-trifluoromethylbenzenesulfonamide;(2S)N-cyclopropyl-N-[1-(4-methyl-2-methylaminopentanoyl)-piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;(2S)N-cyclopropyl-N-[1-(2-ethylamino-4-methylpentanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;(2S)N-[1-(3-amino-5-methylhexanoyl)piperidin-3-yl]-N-cyclopropyl-3-trifluoromethylbenzenesulfonamide;(2S)N-cyclopropyl-N-[1-(2-methylcarbonylpropylamino-4-methyl-pentanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;(2S)N-cyclopropyl-N-{1-[2-(3-methylbutyl)amino-4-methyl-pentanoyl]piperidin-3-yl}-3-trifluoromethylbenzenesulfonamide;(2S)N-cyclopropyl-N-[1-(2-isopropylamino-4-methylpentanoyl)-piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;(2S)N-cyclopropyl-N-[1-(3-methylamino-5-methylhexanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;(2R)N-cyclopropyl-N-[1-(3-methylamino-5-methylhexanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;or a pharmaceutically acceptable salt, prodrug or solvate thereof.
 33. Apharmaceutical composition, comprising the compound of claim 1, or apharmaceutically acceptable salt, prodrug, or solvate thereof, and apharmaceutically acceptable carrier.
 34. A method for treating orameliorating pain, or migraine in a mammal, comprising administering aneffective amount of a compound as claimed in claim 1 or apharmaceutically acceptable salt thereof to a mammal in need of suchtreatment or amelioration.
 35. The method of claim 34, wherein themethod is for treating, or ameliorating pain selected from chronic pain,neuropathic pain, acute pain, and surgical pain.
 36. A method ofpreparing a pharmaceutical composition, comprising admixing atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt, prodrug or solvate thereof, with apharmaceutically acceptable carrier.